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Moultrie F, Chiverton L, Hatami I, Lilien C, Servais L. Pushing the boundaries: future directions in the management of spinal muscular atrophy. Trends Mol Med 2025:S1471-4914(24)00339-3. [PMID: 39794178 DOI: 10.1016/j.molmed.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/07/2024] [Revised: 12/10/2024] [Accepted: 12/11/2024] [Indexed: 01/13/2025]
Abstract
Spinal muscular atrophy (SMA) is a devastating, degenerative, paediatric neuromuscular disease which until recently was untreatable. Discovery of the responsible gene 30 years ago heralded a new age of pioneering therapeutic developments. Three disease-modifying therapies (DMTs) have received regulatory approval and have transformed the disease, reducing disability and prolonging patient survival. These therapies - with distinct mechanisms, routes of administration, dosing schedules, side effect profiles, and financial costs - have dramatically altered the clinical phenotypes of this condition and have presented fresh challenges for patient care. In this review article we discuss potential strategies to maximise clinical outcomes through early diagnosis and treatment, optimised dosing, use of therapeutic combinations and state-of-the-art physiotherapy techniques, and the development of innovative therapies targeting alternative mechanisms.
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Affiliation(s)
- Fiona Moultrie
- MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK; NIHR Oxford Biomedical Research Centre, Oxford, OX3 9DU, UK.
| | - Laura Chiverton
- MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK; NIHR Oxford Biomedical Research Centre, Oxford, OX3 9DU, UK
| | - Isabel Hatami
- MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK; NIHR Oxford Biomedical Research Centre, Oxford, OX3 9DU, UK
| | - Charlotte Lilien
- MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK; NIHR Oxford Biomedical Research Centre, Oxford, OX3 9DU, UK
| | - Laurent Servais
- MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK; NIHR Oxford Biomedical Research Centre, Oxford, OX3 9DU, UK; Neuromuscular Centre, Division of Paediatrics, University Hospital of Liège and University of Liège, 4000, Liège, Belgium.
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Qiu J, Wu L, Qu R, Jiang T, Bai J, Sheng L, Feng P, Sun J. History of development of the life-saving drug “Nusinersen” in spinal muscular atrophy. Front Cell Neurosci 2022; 16:942976. [PMID: 36035257 PMCID: PMC9414009 DOI: 10.3389/fncel.2022.942976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/13/2022] [Accepted: 07/20/2022] [Indexed: 11/21/2022] Open
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive disorder with an incidence of 1/6,000–1/10,000 and is the leading fatal disease among infants. Previously, there was no effective treatment for SMA. The first effective drug, nusinersen, was approved by the US FDA in December 2016, providing hope to SMA patients worldwide. The drug was introduced in the European Union in 2017 and China in 2019 and has so far saved the lives of several patients in most parts of the world. Nusinersen are fixed sequence antisense oligonucleotides with special chemical modifications. The development of nusinersen progressed through major scientific discoveries in medicine, genetics, biology, and other disciplines, wherein several scientists have made substantial contributions. In this article, we will briefly describe the pathogenesis and therapeutic strategies of SMA, summarize the timeline of important scientific findings during the development of nusinersen in a detailed, scientific, and objective manner, and finally discuss the implications of the development of nusinersen for SMA research.
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Affiliation(s)
- Jiaying Qiu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
- Department of Prenatal Screening and Diagnosis Center, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, China
| | - Liucheng Wu
- Laboratory Animal Center, Nantong University, Nantong, China
| | - Ruobing Qu
- Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, China
| | - Tao Jiang
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Jialin Bai
- College of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Lei Sheng
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Pengchao Feng
- Nanjing Antisense Biopharmaceutical Co., Ltd, Nanjing, China
| | - Junjie Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, China
- *Correspondence: Junjie Sun
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López-Cortés A, Echeverría-Garcés G, Ramos-Medina MJ. Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy. BIOLOGY 2022; 11:biology11060894. [PMID: 35741415 PMCID: PMC9219894 DOI: 10.3390/biology11060894] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 04/05/2022] [Revised: 05/04/2022] [Accepted: 05/06/2022] [Indexed: 11/16/2022]
Abstract
The condition known as 5q spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. It is one of the most common pediatric recessive genetic diseases, and it represents the most common cause of hereditary infant mortality. After decades of intensive basic and clinical research efforts, and improvements in the standard of care, successful therapeutic milestones have been developed, delaying the progression of 5q SMA and increasing patient survival. At the same time, promising data from early-stage clinical trials have indicated that additional therapeutic options are likely to emerge in the near future. Here, we provide updated information on the molecular underpinnings of SMA; we also provide an overview of the rapidly evolving therapeutic landscape for SMA, including SMN-targeted therapies, SMN-independent therapies, and combinational therapies that are likely to be key for the development of treatments that are effective across a patient’s lifespan.
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Affiliation(s)
- Andrés López-Cortés
- Programa de Investigación en Salud Global, Facultad de Ciencias de la Salud, Universidad Internacional SEK, Quito 170302, Ecuador
- Facultad de Medicina, Universidad de Las Américas, Quito 170124, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28001 Madrid, Spain; (G.E.-G.); (M.J.R.-M.)
- Correspondence:
| | - Gabriela Echeverría-Garcés
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28001 Madrid, Spain; (G.E.-G.); (M.J.R.-M.)
| | - María José Ramos-Medina
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28001 Madrid, Spain; (G.E.-G.); (M.J.R.-M.)
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Abstract
Autosomal-recessive spinal muscular atrophy (SMA) is characterized by the loss of specific motor neurons of the spinal cord and skeletal muscle atrophy. SMA is caused by mutations or deletions of the survival motor neuron 1 (SMN1) gene, and disease severity correlates with the expression levels of the nearly identical copy gene, SMN2. Both genes ubiquitously express SMN protein, but SMN2 generates only low levels of protein that do not fully compensate for the loss-of-function of SMN1. SMN protein forms a multiprotein complex essential for the cellular assembly of ribonucleoprotein particles involved in diverse aspects of RNA metabolism. Other studies using animal models revealed a spatio-temporal requirement of SMN that is high during the development of the neuromuscular system and later, in the general maintenance of cellular and tissues homeostasis. These observations define a period for maximum therapeutic efficiency of SMN restoration, and suggest that cells outside the central nervous system may also participate in the pathogenesis of SMA. Finally, recent innovative therapies have been shown to mitigate SMN deficiency and have been approved to treat SMA patients. We briefly review major findings from the past twenty-five years of SMA research. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.
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Affiliation(s)
- S Lefebvre
- T3S INSERM UMR 1124, Toxicité Environnementale, Cibles Thérapeutiques, Signalisation Cellulaire et Biomarqueurs, UFR des Sciences Fondamentales et Biomédicales, Campus Saint-Germain-des-prés, Université de Paris, Paris, France.
| | - C Sarret
- Centre de compétence maladies rares des pathologies neuromusculaires, service de génétique médicale, Hôpital Estaing, CHU Clermont-Ferrand, France.
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Behera B. Nusinersen, an exon 7 inclusion drug for spinal muscular atrophy: A minireview. World J Meta-Anal 2021; 9:277-285. [DOI: 10.13105/wjma.v9.i3.277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/03/2020] [Revised: 05/20/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
Spinal muscular atrophy is an autosomal recessive neuromuscular disease with incidence of 1 in 5000 to 10000 live births and is produced by homozygous deletion of exons 7 and 8 in the SMN1 gene. The SMN1 and SMN2 genes encode the survival motor neuron protein, a crucial protein for the preservation of motor neurons. Use of the newer drug, Nusinersen, from early infancy has shown improvement in clinical outcomes of spinal muscular atrophy patients.
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Affiliation(s)
- Bijaylaxmi Behera
- Department of Neonatology, Chaitanya Hospital, Chandigarh 160044, India
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In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy. Brain Sci 2021; 11:brainsci11020194. [PMID: 33562482 PMCID: PMC7915832 DOI: 10.3390/brainsci11020194] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/02/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 12/19/2022] Open
Abstract
Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals.
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Menduti G, Rasà DM, Stanga S, Boido M. Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment. Front Pharmacol 2020; 11:592234. [PMID: 33281605 PMCID: PMC7689316 DOI: 10.3389/fphar.2020.592234] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/06/2020] [Accepted: 09/29/2020] [Indexed: 12/12/2022] Open
Abstract
Spinal muscular atrophy (SMA) is the most common genetic disease affecting infants and young adults. Due to mutation/deletion of the survival motor neuron (SMN) gene, SMA is characterized by the SMN protein lack, resulting in motor neuron impairment, skeletal muscle atrophy and premature death. Even if the genetic causes of SMA are well known, many aspects of its pathogenesis remain unclear and only three drugs have been recently approved by the Food and Drug Administration (Nusinersen-Spinraza; Onasemnogene abeparvovec or AVXS-101-Zolgensma; Risdiplam-Evrysdi): although assuring remarkable results, the therapies show some important limits including high costs, still unknown long-term effects, side effects and disregarding of SMN-independent targets. Therefore, the research of new therapeutic strategies is still a hot topic in the SMA field and many efforts are spent in drug discovery. In this review, we describe two promising strategies to select effective molecules: drug screening (DS) and drug repositioning (DR). By using compounds libraries of chemical/natural compounds and/or Food and Drug Administration-approved substances, DS aims at identifying new potentially effective compounds, whereas DR at testing drugs originally designed for the treatment of other pathologies. The drastic reduction in risks, costs and time expenditure assured by these strategies make them particularly interesting, especially for those diseases for which the canonical drug discovery process would be long and expensive. Interestingly, among the identified molecules by DS/DR in the context of SMA, besides the modulators of SMN2 transcription, we highlighted a convergence of some targeted molecular cascades contributing to SMA pathology, including cell death related-pathways, mitochondria and cytoskeleton dynamics, neurotransmitter and hormone modulation.
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Affiliation(s)
| | | | | | - Marina Boido
- Department of Neuroscience Rita Levi Montalcini, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Turin, Italy
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New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand? Int J Mol Sci 2020; 21:ijms21093297. [PMID: 32392694 PMCID: PMC7246502 DOI: 10.3390/ijms21093297] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/12/2020] [Revised: 05/03/2020] [Accepted: 05/04/2020] [Indexed: 02/08/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.
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Wadman RI, van der Pol WL, Bosboom WMJ, Asselman F, van den Berg LH, Iannaccone ST, Vrancken AFJE. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev 2020; 1:CD006282. [PMID: 32006461 PMCID: PMC6995983 DOI: 10.1002/14651858.cd006282.pub5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. OBJECTIVES To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. SEARCH METHODS We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. SELECTION CRITERIA We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing. AUTHORS' CONCLUSIONS Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.
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Affiliation(s)
- Renske I Wadman
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - W Ludo van der Pol
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Wendy MJ Bosboom
- Onze Lieve Vrouwe Gasthuis locatie WestDepartment of NeurologyAmsterdamNetherlands
| | - Fay‐Lynn Asselman
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Leonard H van den Berg
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Susan T Iannaccone
- University of Texas Southwestern Medical CenterDepartment of Pediatrics5323 Harry Hines BoulevardDallasTexasUSA75390
| | - Alexander FJE Vrancken
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
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Wadman RI, van der Pol WL, Bosboom WMJ, Asselman F, van den Berg LH, Iannaccone ST, Vrancken AFJE. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev 2019; 12:CD006281. [PMID: 31825542 PMCID: PMC6905354 DOI: 10.1002/14651858.cd006281.pub5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a point mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. By definition, children with SMA type I are never able to sit without support and usually die or become ventilator dependent before the age of two years. There have until very recently been no drug treatments to influence the course of SMA. We undertook this updated review to evaluate new evidence on emerging treatments for SMA type I. The review was first published in 2009 and previously updated in 2011. OBJECTIVES To assess the efficacy and safety of any drug therapy designed to slow or arrest progression of spinal muscular atrophy (SMA) type I. SEARCH METHODS We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. We also searched two trials registries to identify unpublished trials (October 2018). SELECTION CRITERIA We sought all randomised controlled trials (RCTs) or quasi-RCTs that examined the efficacy of drug treatment for SMA type I. Included participants had to fulfil clinical criteria and have a genetically confirmed deletion or mutation of the SMN1 gene (5q11.2-13.2). The primary outcome measure was age at death or full-time ventilation. Secondary outcome measures were acquisition of motor milestones, i.e. head control, rolling, sitting or standing, motor milestone response on disability scores within one year after the onset of treatment, and adverse events and serious adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1 gene replacement with viral vectors are out of the scope of this review. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS We identified two RCTs: one trial of intrathecal nusinersen in comparison to a sham (control) procedure in 121 randomised infants with SMA type I, which was newly included at this update, and one small trial comparing riluzole treatment to placebo in 10 children with SMA type I. The RCT of intrathecally-injected nusinersen was stopped early for efficacy (based on a predefined Hammersmith Infant Neurological Examination-Section 2 (HINE-2) response). At the interim analyses after 183 days of treatment, 41% (21/51) of nusinersen-treated infants showed a predefined improvement on HINE-2, compared to 0% (0/27) of participants in the control group. This trial was largely at low risk of bias. Final analyses (ranging from 6 months to 13 months of treatment), showed that fewer participants died or required full-time ventilation (defined as more than 16 hours daily for 21 days or more) in the nusinersen-treated group than the control group (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.32 to 0.89; N = 121; a 47% lower risk; moderate-certainty evidence). A proportion of infants in the nusinersen group and none of 37 infants in the control group achieved motor milestones: 37/73 nusinersen-treated infants (51%) achieved a motor milestone response on HINE-2 (risk ratio (RR) 38.51, 95% CI 2.43 to 610.14; N = 110; moderate-certainty evidence); 16/73 achieved head control (RR 16.95, 95% CI 1.04 to 274.84; moderate-certainty evidence); 6/73 achieved independent sitting (RR 6.68, 95% CI 0.39 to 115.38; moderate-certainty evidence); 7/73 achieved rolling over (RR 7.70, 95% CI 0.45 to 131.29); and 1/73 achieved standing (RR 1.54, 95% CI 0.06 to 36.92; moderate-certainty evidence). Seventy-one per cent of nusinersen-treated infants versus 3% of infants in the control group were responders on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) measure of motor disability (RR 26.36, 95% CI 3.79 to 183.18; N = 110; moderate-certainty evidence). Adverse events and serious adverse events occurred in the majority of infants but were no more frequent in the nusinersen-treated group than the control group (RR 0.99, 95% CI 0.92 to 1.05 and RR 0.70, 95% CI 0.55 to 0.89, respectively; N = 121; moderate-certainty evidence). In the riluzole trial, three of seven children treated with riluzole were still alive at the ages of 30, 48, and 64 months, whereas all three children in the placebo group died. None of the children in the riluzole or placebo group developed the ability to sit, which was the only milestone reported. There were no adverse effects. The certainty of the evidence for all measured outcomes from this study was very low, because the study was too small to detect or rule out an effect, and had serious limitations, including baseline differences. This trial was stopped prematurely because the pharmaceutical company withdrew funding. Various trials and studies investigating treatment strategies other than nusinersen, such as SMN2 augmentation by small molecules, are ongoing. AUTHORS' CONCLUSIONS Based on the very limited evidence currently available regarding drug treatments for SMA type 1, intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with SMA type I. It is also probable that a greater proportion of infants treated with nusinersen than with a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments (HINE-2 and CHOP INTEND). The proportion of children experiencing adverse events and serious adverse events on nusinersen is no higher with nusinersen treatment than with a sham procedure, based on evidence of moderate certainty. It is uncertain whether riluzole has any effect in patients with SMA type I, based on the limited available evidence. Future trials could provide more high-certainty, longer-term evidence to confirm this result, or focus on comparing new treatments to nusinersen or evaluate them as an add-on therapy to nusinersen.
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Affiliation(s)
- Renske I Wadman
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - W Ludo van der Pol
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Wendy MJ Bosboom
- Onze Lieve Vrouwe Gasthuis locatie WestDepartment of NeurologyAmsterdamNetherlands
| | - Fay‐Lynn Asselman
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Leonard H van den Berg
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Susan T Iannaccone
- University of Texas Southwestern Medical CenterDepartment of Pediatrics5323 Harry Hines BoulevardDallasTexasUSA75390
| | - Alexander FJE Vrancken
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
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11
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Bozorg Qomi S, Asghari A, Salmaninejad A, Mojarrad M. Spinal Muscular Atrophy and Common Therapeutic Advances. Fetal Pediatr Pathol 2019; 38:226-238. [PMID: 31060440 DOI: 10.1080/15513815.2018.1520374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is an autosomal recessive destructive motor neuron disease which is characterized primarily by the degeneration of α-motor neurons in the ventral gray horn of the spinal cord. It mainly affects children and represents the most common reason of inherited infant mortality. MATERIAL AND METHODS We provide an overview of the recent therapeutic strategies for the treatment of SMA together with available and developing therapeutic strategies. For this purpose, Google Scholar and PubMed databases were searched for literature on SMA, therapy and treatment. Titles were reviewed and 96 were selected and assessed in this paper. RESULT Over the last two decades, different therapeutic strategies have been proposed for SMA. Some methods are in the pre-clinical, others the clinical phase. CONCLUSION By emergence of the new approaches, especially in gene therapy, effective treatment in the close future is probable.
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Affiliation(s)
- Saeed Bozorg Qomi
- a Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran.,b Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Amir Asghari
- c Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Arash Salmaninejad
- d Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Sciences , Tabriz , Iran
| | - Majid Mojarrad
- a Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran.,b Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
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12
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Abstract
Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. Proximal 5q SMA is caused by decreased levels of the survival of motor neuron (SMN) protein and is the most common genetic cause of infant mortality. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. Unlike other autosomal recessive diseases, the SMN gene has a unique structure (an inverted duplication) that presents potential therapeutic targets. Although there is currently no effective treatment of SMA, the field of translational research in this disorder is active and clinical trials are ongoing. Advances in the multidisciplinary supportive care of children with SMA also offer hope for improved life expectancy and quality of life.
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Affiliation(s)
- Basil T Darras
- Division of Clinical Neurology, Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Fegan 11, Boston, MA 02115, USA.
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13
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Kaczmarek A, Schneider S, Wirth B, Riessland M. Investigational therapies for the treatment of spinal muscular atrophy. Expert Opin Investig Drugs 2015; 24:867-81. [DOI: 10.1517/13543784.2015.1038341] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/21/2022]
Affiliation(s)
- Anna Kaczmarek
- 1University of Cologne, Institute of Human Genetics, Kerpener Str. 34, Cologne 50931, Germany ;
- 2University of Cologne, Institute for Genetics, Cologne, Germany
- 3University of Cologne, Center for Molecular Medicine Cologne, Cologne, Germany
| | - Svenja Schneider
- 1University of Cologne, Institute of Human Genetics, Kerpener Str. 34, Cologne 50931, Germany ;
- 2University of Cologne, Institute for Genetics, Cologne, Germany
- 3University of Cologne, Center for Molecular Medicine Cologne, Cologne, Germany
| | - Brunhilde Wirth
- 1University of Cologne, Institute of Human Genetics, Kerpener Str. 34, Cologne 50931, Germany ;
- 2University of Cologne, Institute for Genetics, Cologne, Germany
- 3University of Cologne, Center for Molecular Medicine Cologne, Cologne, Germany
| | - Markus Riessland
- 1University of Cologne, Institute of Human Genetics, Kerpener Str. 34, Cologne 50931, Germany ;
- 2University of Cologne, Institute for Genetics, Cologne, Germany
- 3University of Cologne, Center for Molecular Medicine Cologne, Cologne, Germany
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14
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Wynne GM, Russell AJ. Drug Discovery Approaches for Rare Neuromuscular Diseases. ORPHAN DRUGS AND RARE DISEASES 2014. [DOI: 10.1039/9781782624202-00257] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 01/29/2023]
Abstract
Rare neuromuscular diseases encompass many diverse and debilitating musculoskeletal disorders, ranging from ultra-orphan conditions that affect only a few families, to the so-called ‘common’ orphan diseases like Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), which affect several thousand individuals worldwide. Increasingly, pharmaceutical and biotechnology companies, in an effort to improve productivity and rebuild dwindling pipelines, are shifting their business models away from the formerly popular ‘blockbuster’ strategy, with rare diseases being an area of increased focus in recent years. As a consequence of this paradigm shift, coupled with high-profile campaigns by not-for-profit organisations and patient advocacy groups, rare neuromuscular diseases are attracting considerable attention as new therapeutic areas for improved drug therapy. Much pioneering work has taken place to elucidate the underlying pathological mechanisms of many rare neuromuscular diseases. This, in conjunction with the availability of new screening technologies, has inspired the development of several truly innovative therapeutic strategies aimed at correcting the underlying pathology. A survey of medicinal chemistry approaches and the resulting clinical progress for new therapeutic agents targeting this devastating class of degenerative diseases is presented, using DMD and SMA as examples. Complementary strategies using small-molecule drugs and biological agents are included.
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Affiliation(s)
- Graham M. Wynne
- Chemistry Research Laboratory, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK
| | - Angela J. Russell
- Chemistry Research Laboratory, University of Oxford 12 Mansfield Road Oxford OX1 3TA UK
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15
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Genç B, Özdinler PH. Moving forward in clinical trials for ALS: motor neurons lead the way please. Drug Discov Today 2013; 19:441-9. [PMID: 24171950 DOI: 10.1016/j.drudis.2013.10.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/25/2013] [Revised: 09/07/2013] [Accepted: 10/21/2013] [Indexed: 12/12/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is one of the most complex motor neuron diseases. Even though scientific discoveries are accelerating with an unprecedented pace, to date more than 30 clinical trials have ended with failure and staggering frustration. There are too many compounds that increase life span in mice, but too little evidence that they will improve human condition. Increasing the chances of success for future clinical trials requires advancement of preclinical tests. Recent developments, which enable the visualization of diseased motor neurons, have the potential to bring novel insight. As we change our focus from mice to motor neurons, it is possible to foster a new vision that translates into effective and long-term treatment strategies in ALS and related motor neuron disorders (MND).
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Affiliation(s)
- Bariş Genç
- Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, USA
| | - P Hande Özdinler
- Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, USA; Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, IL 60611, USA.
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16
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Dachs E, Piedrafita L, Hereu M, Esquerda J, Calderó J. Chronic treatment with lithium does not improve neuromuscular phenotype in a mouse model of severe spinal muscular atrophy. Neuroscience 2013; 250:417-33. [DOI: 10.1016/j.neuroscience.2013.07.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/17/2013] [Revised: 06/26/2013] [Accepted: 07/11/2013] [Indexed: 12/12/2022]
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17
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Seo J, Howell MD, Singh NN, Singh RN. Spinal muscular atrophy: an update on therapeutic progress. Biochim Biophys Acta Mol Basis Dis 2013; 1832:2180-90. [PMID: 23994186 DOI: 10.1016/j.bbadis.2013.08.005] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/13/2013] [Revised: 07/27/2013] [Accepted: 08/14/2013] [Indexed: 12/24/2022]
Abstract
Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.
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Affiliation(s)
- Joonbae Seo
- Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA
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18
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The neuroprotective drug riluzole acts via small conductance Ca2+-activated K+ channels to ameliorate defects in spinal muscular atrophy models. J Neurosci 2013; 33:6557-62. [PMID: 23575853 DOI: 10.1523/jneurosci.1536-12.2013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/21/2022] Open
Abstract
Spinal muscular atrophy (SMA), a recessive neuromuscular disorder, is caused by diminished function of the Survival Motor Neuron (SMN) protein. To define the cellular processes pertinent to SMA, parallel genetic screens were undertaken in Drosophila and Caenorhabditis elegans SMA models to identify modifiers of the SMN loss of function phenotypes. One class of such genetic modifiers was the small conductance, Ca(2+)-activated K(+) (SK) channels. SK channels allow efflux of potassium ions when intracellular calcium increases and can be activated by the neuroprotective drug riluzole. The latter is the only drug with proven, albeit modest, efficacy in the treatment of amyotrophic lateral sclerosis. It is unclear if riluzole can extend life span or ameliorate symptoms in SMA patients as previous studies were limited and of insufficient power to draw any conclusions. The critical biochemical target of riluzole in motor neuron disease is not known, but the pharmacological targets of riluzole include SK channels. We examine here the impact of riluzole in two different SMA models. In vertebrate neurons, riluzole treatment restored axon outgrowth caused by diminished SMN. Additionally, riluzole ameliorated the neuromuscular defects in a C. elegans SMA model and SK channel function was required for this beneficial effect. We propose that riluzole improves motor neuron function by acting on SK channels and suggest that SK channels may be important therapeutic targets for SMA patients.
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19
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Abstract
Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease that results in progressive dysfunction of motor neurons of the anterior horn of the spinal cord. SMA is caused by the loss of full-length protein expression from the survival of motor neuron 1 (SMN1) gene. The disease has a unique genetic profile as it is autosomal recessive for the loss of SMN1, but a nearly identical homolog, SMN2, acts as a disease modifier whose expression is inversely correlated to clinical severity. Targeted therapeutic approaches primarily focus on increasing the levels of full-length SMN protein, through either gene replacement or regulation of SMN2 expression. There is currently no US FDA approved treatment for SMA. This is an exciting time as multiple efforts from academic and industrial laboratories are reaching the preclinical and clinical testing stages.
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20
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Abstract
Spinal muscular atrophies (SMA) are genetic disorders characterized by degeneration of lower motor neurons. The most frequent form is caused by mutations of the survival motor neuron 1 gene (SMN1). The identification of this gene greatly improved diagnostic testing and family-planning options of SMA families. SMN plays a key role in metabolism of RNA. However, the link between RNA metabolism and motor neuron degeneration remains unknown. A defect in mRNA processing likely generates either a loss of function of some critical RNA or abnormal transcripts with toxic property for motor neurons. Mutations of SMN in various organisms highlighted an essential role of SMN in motor axon and neuromuscular junction development or maintenance. The quality of life of patients has greatly improved over recent decades through the improvement of care and management of patients. In addition, major advances in translational research have been made in the field of SMA. Various therapeutic strategies have been successfully developed aiming at acting on SMN2, a partially functional copy of the SMN1 gene which remains present in patients. Drugs have been identified and some are already at preclinical stages. Identifying molecules involved in the SMA degenerative process should represent additional attractive targets for therapeutics in SMA.
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Affiliation(s)
- Louis Viollet
- Hôpital Necker-Enfants Malades and Université Paris Descartes, Paris, France
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21
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Therapy development for spinal muscular atrophy in SMN independent targets. Neural Plast 2012; 2012:456478. [PMID: 22701806 PMCID: PMC3369530 DOI: 10.1155/2012/456478] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/01/2012] [Revised: 04/05/2012] [Accepted: 04/06/2012] [Indexed: 12/11/2022] Open
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.
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22
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Wadman RI, Bosboom WMJ, van der Pol WL, van den Berg LH, Wokke JHJ, Iannaccone ST, Vrancken AFJE. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev 2012:CD006282. [PMID: 22513940 DOI: 10.1002/14651858.cd006282.pub4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. This is an update of a review first published in 2009. OBJECTIVES To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA types II and III and to assess if such therapy can be given safely. Drug treatment for SMA type I is the topic of a separate updated Cochrane review. SEARCH METHODS We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to March 8 2011). We also searched clinicaltrials.gov to identify as yet unpublished trials (8 March 2011). SELECTION CRITERIA We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a deletion or mutation of the survival motor neuron 1 (SMN1) gene (5q11.2-13.2) that was confirmed by genetic analysis.The primary outcome measure was to be change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were to be change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full time ventilation and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS Two authors independently reviewed and extracted data from all potentially relevant trials. Pooled relative risks and pooled standardised mean differences were to be calculated to assess treatment efficacy. Risk of bias was systematically analysed. MAIN RESULTS Six randomised placebo-controlled trials on treatment for SMA types II and III were found and included in the review: the four in the original review and two trials added in this update. The treatments were creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants), and combination therapy with valproate and acetyl-L-carnitine (61 participants). None of these studies were completely free of bias. All studies had adequate blinding, sequence generation and reports of primary outcomes.None of the included trials showed any statistically significant effects on the outcome measures in participants with SMA types II and III. One participant died due to suffocation in the hydroxyurea trial and one participant died in the creatine trial. No participants in any of the other four trials died or reached the state of full time ventilation. Serious side effects were infrequent. AUTHORS' CONCLUSIONS There is no proven efficacious drug treatment for SMA types II and III.
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Affiliation(s)
- Renske I Wadman
- Department of Neurology, University Medical Center Utrecht, Utrecht, Netherlands.
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23
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Wadman RI, Bosboom WMJ, van der Pol WL, van den Berg LH, Wokke JHJ, Iannaccone ST, Vrancken AFFJE. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev 2012:CD006281. [PMID: 22513939 DOI: 10.1002/14651858.cd006281.pub4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells of the spinal cord, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the course of the disease. This is an update of a review first published in 2009. OBJECTIVES To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA type I, and to assess if such therapy can be given safely. Drug treatment for SMA types II and III is the topic of a separate updated Cochrane review. SEARCH METHODS We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to 8 March 2011). We searched the Clinical Trials Registry of the U.S. National Institute of Health (www.ClinicalTrials.gov) (8 March 2011) to identify additional trials that had not yet been published. SELECTION CRITERIA We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA type I. Participants had to fulfil the clinical criteria and have a deletion or mutation of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis.The primary outcome measure was time from birth until death or full time ventilation. Secondary outcome measures were development of rolling, sitting or standing within one year after the onset of treatment, and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS Two authors (RW and AV) independently reviewed and extracted data from all potentially relevant trials. For included studies, pooled relative risks and standardised mean differences were to be calculated to assess treatment efficacy. MAIN RESULTS One small randomised controlled study comparing riluzole treatment to placebo for 10 SMA type 1 children was identified and included in the original review. No further trials were identified for the update in 2011. Regarding the primary outcome measure, three of seven children treated with riluzole were still alive at the ages of 30, 48 and 64 months, whereas all three children in the placebo group died; but the difference was not statistically significant. Regarding the secondary outcome measures, none of the children in the riluzole or placebo group developed the ability to roll, sit or stand, and no adverse effects were observed. For several reasons the overall quality of the study was low, mainly because the study was too small to detect an effect and because of baseline differences. Follow-up of the 10 included children was complete. AUTHORS' CONCLUSIONS No drug treatment for SMA type I has been proven to have significant efficacy.
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Affiliation(s)
- Renske I Wadman
- Department of Neurology, University Medical Center Utrecht, Utrecht, Netherlands.
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24
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Abstract
Spinal muscular atrophy, a hereditary degenerative disorder of lower motor neurons associated with progressive muscle weakness and atrophy, is the most common genetic cause of infant mortality. It is caused by decreased levels of the "survival of motor neuron" (SMN) protein. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. However, unlike many other autosomal recessive diseases, the SMN gene involves a unique structure (an inverted duplication) that presents potential therapeutic targets. Although no effective treatment for spinal muscular atrophy exists, the field of translational research in spinal muscular atrophy is active, and clinical trials are ongoing. Advances in the multidisciplinary supportive care of children with spinal muscular atrophy also offer hope for improved life expectancy and quality of life.
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Wadman RI, Bosboom WM, van den Berg LH, Wokke JH, Iannaccone ST, Vrancken AF. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev 2011:CD006281. [PMID: 22161399 DOI: 10.1002/14651858.cd006281.pub3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells of the spinal cord, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the course of the disease. This is an update of a review first published in 2009. OBJECTIVES To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA type I, and to assess if such therapy can be given safely. Drug treatment for SMA types II and III is the topic of a separate updated Cochrane review. SEARCH METHODS We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to 8 March 2011). We searched the Clinical Trials Registry of the U.S. National Institute of Health (www.ClinicalTrials.gov) (8 March 2011) to identify additional trials that had not yet been published. SELECTION CRITERIA We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA type I. Participants had to fulfil the clinical criteria and have a deletion or mutation of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis.The primary outcome measure was time from birth until death or full time ventilation. Secondary outcome measures were development of rolling, sitting or standing within one year after the onset of treatment, and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS Two authors (RW and AV) independently reviewed and extracted data from all potentially relevant trials. For included studies, pooled relative risks and standardised mean differences were to be calculated to assess treatment efficacy. MAIN RESULTS One small randomised controlled study comparing riluzole treatment to placebo for 10 SMA type 1 children was identified and included in the original review. No further trials were identified for the update in 2011. Regarding the primary outcome measure, three of seven children treated with riluzole were still alive at the ages of 30, 48 and 64 months, whereas all three children in the placebo group died; but the difference was not statistically significant. Regarding the secondary outcome measures, none of the children in the riluzole or placebo group developed the ability to roll, sit or stand, and no adverse effects were observed. For several reasons the overall quality of the study was low, mainly because the study was too small to detect an effect and because of baseline differences. Follow-up of the 10 included children was complete. AUTHORS' CONCLUSIONS No drug treatment for SMA type I has been proven to have significant efficacy.
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Affiliation(s)
- Renske I Wadman
- Department of Neurology, University Medical Center Utrecht, Rudolf Magnus Institute for Neuroscience, Universiteitsweg 100, Utrecht, Netherlands, 3584 CG
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26
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Wadman RI, Bosboom WM, van den Berg LH, Wokke JH, Iannaccone ST, Vrancken AF. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev 2011:CD006282. [PMID: 22161400 DOI: 10.1002/14651858.cd006282.pub3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. This is an update of a review first published in 2009. OBJECTIVES To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA types II and III and to assess if such therapy can be given safely. Drug treatment for SMA type I is the topic of a separate updated Cochrane review. SEARCH METHODS We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to March 8 2011). We also searched clinicaltrials.gov to identify as yet unpublished trials (8 March 2011). SELECTION CRITERIA We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a deletion or mutation of the survival motor neuron 1 (SMN1) gene (5q11.2-13.2) that was confirmed by genetic analysis.The primary outcome measure was to be change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were to be change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full time ventilation and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS Two authors independently reviewed and extracted data from all potentially relevant trials. Pooled relative risks and pooled standardised mean differences were to be calculated to assess treatment efficacy. Risk of bias was systematically analysed. MAIN RESULTS Six randomised placebo-controlled trials on treatment for SMA types II and III were found and included in the review: the four in the original review and two trials added in this update. The treatments were creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants), and combination therapy with valproate and acetyl-L-carnitine (61 participants). None of these studies were completely free of bias. All studies had adequate blinding, sequence generation and reports of primary outcomes.None of the included trials showed any statistically significant effects on the outcome measures in participants with SMA types II and III. One participant died due to suffocation in the hydroxyurea trial and one participant died in the creatine trial. No participants in any of the other four trials died or reached the state of full time ventilation. Serious side effects were infrequent. AUTHORS' CONCLUSIONS There is no proven efficacious drug treatment for SMA types II and III.
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Affiliation(s)
- Renske I Wadman
- Department of Neurology, University Medical Center Utrecht, Rudolf Magnus Institute for Neuroscience, Universiteitsweg 100, Utrecht, Netherlands, 3584 CG
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Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of spinal cord motor neurons and muscular atrophy. Advances in recent research have led to understanding of the molecular genetics of SMA. Therapeutic strategies have been developed according to the unique genomic structure of the SMN genes. Three groups of compounds have been identified as therapeutic candidates. One group was identified before the molecular genetics of SMA was understood, chosen on the basis of their effectiveness in similar neurologic disorders. The second group was identified based on their ability to modify SMN2 gene expression. Several of these agents are currently in clinical trials. A third group, identified by large-scale drug screening, is still under preclinical investigation. In addition, other advances in medical technology have led to the publication of a consensus statement regarding the care of SMA patients.
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Burnett BG, Crawford TO, Sumner CJ. Emerging treatment options for spinal muscular atrophy. Curr Treat Options Neurol 2011; 11:90-101. [PMID: 19210911 DOI: 10.1007/s11940-009-0012-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/31/2022]
Abstract
The motor neuron disease spinal muscular atrophy (SMA) is one of the leading genetic killers of infants worldwide. SMA is caused by mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the survival motor neuron (SMN) protein. All patients retain one or more copies of the SMN2 gene, which (by producing a small amount of the SMN protein) rescues embryonic lethality and modifies disease severity. Rapid progress continues in dissecting the cellular functions of the SMN protein, but the mechanisms linking SMN deficiency with dysfunction and loss of functioning motor units remain poorly defined. Clinically, SMA should to be distinguished from other neuromuscular disorders, and the diagnosis can be readily confirmed with genetic testing. Quality of life and survival of SMA patients are improved with aggressive supportive care including optimized respiratory and nutritional care and management of scoliosis and contractures. Because SMA is caused by inadequate amounts of SMN protein, one aim of current SMA therapeutics development is to increase SMN protein levels in SMA patients by activating SMN2 gene expression and/or increasing levels of full-length SMN2 transcripts. Several potential therapeutic compounds are currently being studied in clinical trials in SMA patients.
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Affiliation(s)
- Barrington G Burnett
- Charlotte J. Sumner, MD 600 North Wolfe Street, Meyer 5-119b, Baltimore, MD 21287, USA.
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Abbara C, Estournet B, Lacomblez L, Lelièvre B, Ouslimani A, Lehmann B, Viollet L, Barois A, Diquet B. Riluzole pharmacokinetics in young patients with spinal muscular atrophy. Br J Clin Pharmacol 2011; 71:403-10. [PMID: 21284699 DOI: 10.1111/j.1365-2125.2010.03843.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/11/2022] Open
Abstract
AIMS The objective of the present study was to assess the pharmacokinetics of riluzole in patients with spinal muscular atrophy (SMA). METHODS Fourteen patients were enrolled in an open-label, nonrandomized and repeat-dose pharmacokinetic study. All participants were assigned to receive 50mg riluzole orally for 5 days. Riluzole plasma concentrations were determined from samples obtained at day 5. RESULTS The pharmacokinetic analysis demonstrated that a dose of 50mg once a day was sufficient to obtain a daily total exposure [AUC(0,24h)=2257ng ml(-1) h] which was comparable with results obtained in adult healthy volunteers or ALS patients in whom a dose of 50mg twice a day is recommended. The pharmacokinetic simulation demonstrated that the administration of 50mg twice a day could result in higher concentrations, hence reduced safety margin. CONCLUSION The dose of 50mg once a day was chosen for the clinical trial evaluating the efficacy of riluzole in SMA patients.
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Affiliation(s)
- Chadi Abbara
- Université d'Angers, UFR médecine, Angers cedex, F-49045 CHU d'Angers, Service Pharmacologie-Toxicologie, Angers cedex 09, France
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Tiziano FD, Neri G, Brahe C. Biomarkers in rare disorders: the experience with spinal muscular atrophy. Int J Mol Sci 2010; 12:24-38. [PMID: 21339974 PMCID: PMC3039940 DOI: 10.3390/ijms12010024] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/10/2010] [Revised: 12/06/2010] [Accepted: 12/16/2010] [Indexed: 12/20/2022] Open
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous mutations of the SMN1 gene. Based on clinical severity, three forms of SMA are recognized (type I–III). All patients have at least one (usually 2–4) copies of a highly homologous gene (SMN2) which produces insufficient levels of functional SMN protein, due to alternative splicing of exon7. Recently, evidence has been provided that SMN2 expression can be enhanced by different strategies. The availability of potential candidates to treat SMA has raised a number of issues, including the availability of data on the natural history of the disease, the reliability and sensitivity of outcome measures, the duration of the studies, and the number and clinical homogeneity of participating patients. Equally critical is the availability of reliable biomarkers. So far, different tools have been proposed as biomarkers in SMA, classifiable into two groups: instrumental (the Compound Motor Action Potential, the Motor Unit Number Estimation, and the Dual-energy X-ray absorptiometry) and molecular (SMN gene products dosage, either transcripts or protein). However, none of the biomarkers available so far can be considered the gold standard. Preclinical studies on SMA animal models and double-blind, placebo-controlled studies are crucial to evaluate the appropriateness of biomarkers, on the basis of correlations with clinical outcome.
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Affiliation(s)
- Francesco D Tiziano
- Institute of Medical Genetics, Catholic University of Sacro Cuore, Roma, Italy; E-Mails: (G.N.); (C.B.)
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Conserved genes act as modifiers of invertebrate SMN loss of function defects. PLoS Genet 2010; 6:e1001172. [PMID: 21124729 PMCID: PMC2965752 DOI: 10.1371/journal.pgen.1001172] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/04/2010] [Accepted: 09/21/2010] [Indexed: 01/27/2023] Open
Abstract
Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species.
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Abstract
AbstractProgress in understanding the genetic basis and pathophysiology of spinal muscular atrophy (SMA), along with continuous efforts in finding a way to increase survival motor neuron (SMN) protein levels have resulted in several strategies that have been proposed as potential directions for efficient drug development. Here we provide an overview on the current status of the following approaches: 1) activation of SMN2 gene and increasing full length SMN2 transcript level, 2) modulating SMN2 splicing, 3) stabilizing SMN mRNA and SMN protein, 4) development of neurotrophic, neuroprotective and anabolic compounds and 5) stem cell and gene therapy. The new preclinical advances warrant a cautious optimism for emergence of an effective treatment in the very near future.
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Bosboom WMJ, Vrancken AFJE, van den Berg LH, Wokke JHJ, Iannaccone ST. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev 2009:CD006282. [PMID: 19160275 DOI: 10.1002/14651858.cd006282.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. OBJECTIVES To evaluate if drug treatment is able to slow or arrest the disease progression of SMA type II and III, and to assess if such therapy can be given safely. Drug treatment for SMA type I will be the topic of a separate Cochrane review. SEARCH STRATEGY We searched the Cochrane Neuromuscular Disease Group Trials Register (September 30 2008), The Cochrane Library (Issue 3, 2008), MEDLINE (January 1966 to June 2008), EMBASE (January 1980 to June 2008), ISI (January 1988 to June 2008), and ACP Journal Club (January 1991 to June 2008). SELECTION CRITERIA We sought all randomized or quasi-randomized trials that examined the efficacy of drug treatment for SMA type II and III. Participants had to fulfil the clinical criteria and, in studies including genetic analysis to confirm the diagnosis, have a deletion or mutation of the SMN1 gene (5q11.2-13.2)The primary outcome measure was to be change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were to be change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full time ventilation, and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS Two authors independently reviewed and extracted data from all potentially relevant trials. Pooled relative risks and pooled weighted standardized mean differences were to be calculated to assess treatment efficacy MAIN RESULTS Four randomized placebo-controlled trials on treatment for SMA type II and III were found and included in the review. The treatments were creatine, phenylbutyrate, gabapentin and thyrotropin releasing hormone. None of these trials showed any effect on the outcome measures in patients with SMA type II and III. None of the patients in any of the four trials died or reached the state of full time ventilation and serious side effects were infrequent. AUTHORS' CONCLUSIONS There is no proven efficacious drug treatment for SMA type II and III.
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Affiliation(s)
- Wendy M J Bosboom
- Department of Neurology, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, Amsterdam, Netherlands, 1061 AE.
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Bosboom WMJ, Vrancken AFJE, van den Berg LH, Wokke JHJ, Iannaccone ST. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev 2009:CD006281. [PMID: 19160274 DOI: 10.1002/14651858.cd006281.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the disease course. OBJECTIVES To evaluate if drug treatment is able to slow or arrest the disease progression of SMA type I, and to assess if such therapy can be given safely. Drug treatment for SMA type II and III will be will be the topic of a separate Cochrane review. SEARCH STRATEGY We searched the Cochrane Neuromuscular Disease Group Trials Register (September 30 2008, The Cochrane Library (Issue 3, 2008), MEDLINE (January 1966 to June 2008), EMBASE (January 1980 to June 2008), ISI (January 1988 to June 2008), and ACP Journal Club (January 1991 to June 2008). SELECTION CRITERIA All randomized or quasi-randomized trials that examined the efficacy of drug treatment for SMA type 1 were sought. Participants had to fulfil clinical criteria and, in studies including genetic analysis to confirm the diagnosis, have a deletion or mutation of the SMN1 gene (5q11.2-13.2)The primary outcome measure was to be time from birth until death or full time ventilation. Secondary outcome measures were to be development of rolling, sitting or standing within one year after the onset of treatment, and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS Two authors (WB and AV) independently reviewed and extracted data from all potentially relevant trials. For included studies pooled relative risks and pooled weighted standardized mean differences were to be calculated to assess treatment efficacy MAIN RESULTS One small randomized-controlled study comparing riluzole treatment to placebo for SMA type 1 was identified and included in the review. Regarding the primary outcome measure three of seven children treated with riluzole were still alive at the age of 30, 48 and 64 months, whereas all three children in the placebo group died, but the difference was not statistically significant. Regarding the secondary outcome measures none of the patients in the riluzole or placebo group developed the ability to roll, sit or stand, and no adverse effects were observed. AUTHORS' CONCLUSIONS No drug treatment for SMA type I has been proven to have significant efficacy.
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Affiliation(s)
- Wendy M J Bosboom
- Department of Neurology, Sint Lucas Andreas Hospital, Jan Tooropstraat 164, Amsterdam, Netherlands, 1061 AE.
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Vitte J, Attali R, Warwar N, Gurt I, Melki J. Spinal muscular atrophy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 652:237-46. [PMID: 20225030 DOI: 10.1007/978-90-481-2813-6_16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/20/2022]
Abstract
Spinal muscular atrophies (SMA) are frequent autosomal recessive disorders characterized by degeneration of lower motor neurons. SMA are caused by mutations of the survival of motor neuron gene (SMN1) leading to a reduction of the SMN protein amount. The identification of SMN interacting proteins involved in the formation of the spliceosome and splicing changes in SMN-deficient tissues of mutant mice strongly support the view that SMN is involved in the splicing reaction. However, the molecular pathway linking SMN defect to the SMA phenotype remains unclear. From a better knowledge of the genetic basis of SMA and the defects resulting from the mutations of SMN1 in cellular or animal models, several therapeutics strategies have been selected aiming at targeting SMN2, a partially functional copy of SMN1 gene which remains present in patients, or to prevent neurons from death. Refined characterization of the degenerative process in SMA and the identification of the defective molecular pathway downstream from the SMN defect will provide further exciting insight into this disease in the near future. They should contribute to clarify the pathophysiology of SMA, the function of SMN and should help in designing potential targeted or non-targeted therapeutic molecules.
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Affiliation(s)
- Jérémie Vitte
- Department of Human Genetics, Hadassah University Hospital, PO Box 91120, Jerusalem, Israel
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Pane M, Staccioli S, Messina S, D'Amico A, Pelliccioni M, Mazzone ES, Cuttini M, Alfieri P, Battini R, Main M, Muntoni F, Bertini E, Villanova M, Mercuri E. Daily salbutamol in young patients with SMA type II. Neuromuscul Disord 2008; 18:536-40. [PMID: 18579379 DOI: 10.1016/j.nmd.2008.05.004] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/01/2008] [Revised: 05/05/2008] [Accepted: 05/12/2008] [Indexed: 11/15/2022]
Abstract
The aim of this open pilot study was to establish the profile of tolerability and clinical response of salbutamol (albuterol) in a cohort of young children affected by type II spinal muscular atrophy (SMA). Twenty-three children between 30 months and 6 years of age were treated with salbutamol (2 mg three times a day) for 1 year. All children were longitudinally assessed using the Hammersmith motor functional scale 6 months before treatment started (T0), at baseline (T1) and 6 and 12 months later. There was no significant change in function between T0 and T1 assessments, but the functional scores recorded after 6 and 12 months of treatment were significantly higher than those recorded at baseline (p=0.006). Our results suggest that salbutamol may be beneficial to SMA patients without producing any major side effect. Larger prospective randomized, double-blind, placebo controlled trials are needed to confirm these preliminary findings.
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Affiliation(s)
- Marika Pane
- Department of Paediatric Neurology, Catholic University, Policlinico Gemelli Largo Gemelli, 00168 Rome, Italy
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Abstract
Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterised by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalised weakness. It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation. Although no medical treatment is available, investigations have elucidated possible mechanisms underlying the molecular pathogenesis of the disease. Treatment strategies have been developed to use the unique genomic structure of the SMN1 gene region. Several candidate treatment agents have been identified and are in various stages of development. These and other advances in medical technology have changed the standard of care for patients with spinal muscular atrophy. In this Seminar, we provide a comprehensive review that integrates clinical manifestations, molecular pathogenesis, diagnostic strategy, therapeutic development, and evidence from clinical trials.
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Affiliation(s)
- Mitchell R Lunn
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Swoboda KJ, Kissel JT, Crawford TO, Bromberg MB, Acsadi G, D'Anjou G, Krosschell KJ, Reyna SP, Schroth MK, Scott CB, Simard LR. Perspectives on clinical trials in spinal muscular atrophy. J Child Neurol 2007; 22:957-66. [PMID: 17761650 PMCID: PMC3260051 DOI: 10.1177/0883073807305665] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/02/2023]
Abstract
Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.
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Affiliation(s)
- Kathryn J Swoboda
- Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
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Wirth PhD B, Riessland Msc M, Hahnen MBA E. Drug discovery for spinal muscular atrophy. Expert Opin Drug Discov 2007; 2:437-51. [DOI: 10.1517/17460441.2.4.437] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
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Avila AM, Burnett BG, Taye AA, Gabanella F, Knight MA, Hartenstein P, Cizman Z, Di Prospero NA, Pellizzoni L, Fischbeck KH, Sumner CJ. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J Clin Invest 2007; 117:659-71. [PMID: 17318264 PMCID: PMC1797603 DOI: 10.1172/jci29562] [Citation(s) in RCA: 268] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/30/2006] [Accepted: 12/20/2006] [Indexed: 01/20/2023] Open
Abstract
The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by mutation of the telomeric survival motor neuron 1 (SMN1) gene with retention of the centromeric SMN2 gene. We sought to establish whether the potent and specific hydroxamic acid class of histone deacetylase (HDAC) inhibitors activates SMN2 gene expression in vivo and modulates the SMA disease phenotype when delivered after disease onset. Single intraperitoneal doses of 10 mg/kg trichostatin A (TSA) in nontransgenic and SMA model mice resulted in increased levels of acetylated H3 and H4 histones and modest increases in SMN gene expression. Repeated daily doses of TSA caused increases in both SMN2-derived transcript and SMN protein levels in neural tissues and muscle, which were associated with an improvement in small nuclear ribonucleoprotein (snRNP) assembly. When TSA was delivered daily beginning on P5, after the onset of weight loss and motor deficit, there was improved survival, attenuated weight loss, and enhanced motor behavior. Pathological analysis showed increased myofiber size and number and increased anterior horn cell size. These results indicate that the hydroxamic acid class of HDAC inhibitors activates SMN2 gene expression in vivo and has an ameliorating effect on the SMA disease phenotype when administered after disease onset.
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Affiliation(s)
- Amy M. Avila
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Barrington G. Burnett
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Addis A. Taye
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Francesca Gabanella
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Melanie A. Knight
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Parvana Hartenstein
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Ziga Cizman
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Nicholas A. Di Prospero
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Livio Pellizzoni
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Kenneth H. Fischbeck
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
| | - Charlotte J. Sumner
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, USA.
Dulbecco Telethon Institute, Institute of Cell Biology (CNR), Rome, Italy
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Tsai LK, Tsai MS, Lin TB, Hwu WL, Li H. Establishing a standardized therapeutic testing protocol for spinal muscular atrophy. Neurobiol Dis 2006; 24:286-95. [PMID: 16952456 DOI: 10.1016/j.nbd.2006.07.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/30/2006] [Revised: 07/04/2006] [Accepted: 07/10/2006] [Indexed: 01/19/2023] Open
Abstract
Several mice models have been created for spinal muscular atrophy (SMA); however, there is still no standard preclinical testing system for the disease. We previously generated type III-specific SMA model mice, which might be suitable for use as a preclinical therapeutic testing system for SMA. To establish such a system and test its applicability, we first created a testing protocol and then applied it as a means to investigate the use of valproic acid (VPA) as a possible treatment for SMA. These SMA mice revealed tail/ear/foot deformity, muscle atrophy, poorer motor performances, smaller compound muscle action potential and lower spinal motoneuron density at the age of 9 to 12 months in comparison with age-matched wild-type littermate mice. In addition, VPA attenuates motoneuron death, increases spinal SMN protein level and partially normalizes motor function in SMA mice. These results suggest that the testing protocol developed here is well suited for use as a standardized preclinical therapeutic testing system for SMA.
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MESH Headings
- Animals
- Cell Death/drug effects
- Cell Death/physiology
- Cell Survival/drug effects
- Cell Survival/physiology
- Cyclic AMP Response Element-Binding Protein/biosynthesis
- Disease Models, Animal
- Drug Evaluation, Preclinical/methods
- Enzyme Inhibitors/pharmacology
- Enzyme Inhibitors/therapeutic use
- Female
- Histone Deacetylase Inhibitors
- Histone Deacetylases/metabolism
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Motor Neurons/drug effects
- Motor Neurons/pathology
- Muscle, Skeletal/innervation
- Muscle, Skeletal/physiopathology
- Muscular Atrophy, Spinal/diagnosis
- Muscular Atrophy, Spinal/drug therapy
- Muscular Atrophy, Spinal/physiopathology
- Nerve Degeneration/diagnosis
- Nerve Degeneration/drug therapy
- Nerve Degeneration/physiopathology
- Nerve Tissue Proteins/biosynthesis
- Neuroprotective Agents/pharmacology
- Neuroprotective Agents/therapeutic use
- Predictive Value of Tests
- RNA-Binding Proteins/biosynthesis
- SMN Complex Proteins
- Spinal Cord/drug effects
- Spinal Cord/pathology
- Spinal Cord/physiopathology
- Treatment Outcome
- Valproic Acid/pharmacology
- Valproic Acid/therapeutic use
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Affiliation(s)
- Li-Kai Tsai
- Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
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Mattis VB, Rai R, Wang J, Chang CWT, Coady T, Lorson CL. Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts. Hum Genet 2006; 120:589-601. [PMID: 16951947 DOI: 10.1007/s00439-006-0245-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/07/2006] [Accepted: 08/10/2006] [Indexed: 11/24/2022]
Abstract
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA is caused by the homozygous absence of survival motor neuron-1 (SMN1). SMN2, a nearly identical copy gene, is retained in all SMA patients and encodes an identical protein as SMN1; however, SMN1 and SMN2 differ by a silent C to T transition which results in the production of an alternatively spliced isoform (SMNDelta7), which encodes a defective protein, demonstrating that the absence of the short peptide encoded by SMN exon 7 is critical in SMA development. Previously, we have shown that for some functions heterologous sequences can compensate for the exon 7 peptide, suggesting that the SMN C-terminus functions non-specifically. Consistent with this hypothesis, we now identify novel aminoglycosides that can induce SMN protein levels in patient fibroblasts. This hypothesis was supported, in part, by a novel fluorescent SMN read-through assay. Interestingly, however, through the development of a SMN exon 7-specific antibody, results suggested that levels of normal full-length SMN might also be elevated by aminoglycoside treatment. These results demonstrate that the compounds that promote read-through may provide an alternative platform for the discovery of compounds that induce SMN protein levels.
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Affiliation(s)
- Virginia B Mattis
- Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO 65211-7310, USA
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Abstract
Recent developments in our understanding of the pathophysiological mechanisms underlying degeneration in both the central and peripheral nervous systems have highlighted the critical role that synapses play in the instigation and progression of neuronal loss. In fact, several lines of evidence suggest that previous attempts to delay the onset and progression of clinical symptoms in a broad range of neurodegenerative diseases may have been unsuccessful as a result of a failure to protect synaptic compartments. As a result, the synapse needs to be viewed as an important target for the development of novel protective treatments aimed at preventing or slowing disease progression. We summarize important findings from human studies and animal models demonstrating common synaptic vulnerability across several neurodegenerative diseases. We also discuss recent developments in our understanding of degenerative mechanisms that are known to be localized to synapses and suggest potential ways to harness this understanding to develop synaptoprotective strategies for neurodegenerative disease.
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Affiliation(s)
- Thomas M Wishart
- Centre for Integrative Physiology & Centre for Neuroscience Research, University of Edinburgh Medical School, UK
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45
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Abstract
The molecular basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the homozygous loss of the survival motor neuron gene 1 (SMN1). A nearly identical copy of the SMN1 gene, called SMN2, modulates the disease severity. The functional difference between both genes is a translationally silent mutation that, however, disrupts an exonic splicing enhancer causing exon 7 skipping in most SMN2 transcripts. Only 10% of SMN2 transcripts encode functional full-length protein identical to SMN1. Transcriptional activation, facilitation of correct SMN2 splicing, or stabilization of the protein are considered as strategies for SMA therapy. Among various drugs, histone deacetylase inhibitors such as valproic acid (VPA) or 4-phenylbutyrate (PBA) have been shown to increase SMN2-derived RNA and protein levels. Recently, in vivo activation of the SMN gene was shown in VPA-treated SMA patients and carriers. Clinical trials are underway to investigate the effect of VPA and PBA on motor function in SMA patients.
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Affiliation(s)
- Brunhilde Wirth
- Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
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46
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Nelson L, Owens H, Hynan LS, Iannaccone ST. The gross motor function measure™ is a valid and sensitive outcome measure for spinal muscular atrophy. Neuromuscul Disord 2006; 16:374-80. [PMID: 16632361 DOI: 10.1016/j.nmd.2006.03.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/07/2005] [Revised: 12/17/2005] [Accepted: 03/07/2006] [Indexed: 11/17/2022]
Abstract
Spinal muscular atrophy is a genetic disease of the anterior horn cell with high morbidity rate in childhood. Certain drugs may be of benefit and are in or under consideration for Phase II trials. Outcome measures that are age appropriate and representative of disease activity remain under study. Several have not yet been validated for spinal muscular atrophy. The Gross Motor Function Measure is a measure of motor function. We showed previously that the Gross Motor Function Measure is a reliable outcome measure to assess motor function in children with spinal muscular atrophy. By collating our data from 40 spinal muscular atrophy patients, ages 5 through 17 years, we now show the validity of the Gross Motor Function Measure when compared to Quantitative Muscle Testing and ambulatory status in children with spinal muscular atrophy. The median for Gross Motor Function Measure total scores for walkers was 237 (range: 197-261) and for non-walkers, 64 (range: 4-177; P<0.0001) with no distributional overlap. We conclude that the Gross Motor Function Measure is valid and sensitive as an outcome measure for clinical trials in pediatric spinal muscular atrophy.
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Affiliation(s)
- Leslie Nelson
- Texas Scottish Rite Hospital for Children, Dallas, TX, USA
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47
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Abstract
Spinal muscular atrophy is an autosomal recessive motor neuron disease that is the leading inherited cause of infant and early childhood mortality. Spinal muscular atrophy is caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1), but all patients retain a centromeric copy of the gene, SMN2. SMN2 produces reduced amounts of full-length SMN mRNA, and spinal muscular atrophy likely results from insufficient levels of SMN protein in motor neurons. The SMN protein plays a well-established role in assembly of the spliceosome and may also mediate mRNA trafficking in the axon and nerve terminus of neurons. In patients, spinal muscular atrophy disease severity correlates inversely with increased SMN2 gene copy number and, in transgenic mice lacking endogenous SMN, increasing SMN2 gene copy number from two to eight prevents the SMA disease phenotype. These observations suggest that increasing SMN expression levels may be beneficial to SMA patients. Currently pursued therapeutic strategies for SMA include induction of SMN2 gene expression, modulation of splicing of SMN2-derived transcripts, stabilization of SMN protein, neuroprotection of SMN deficit neurons, and SMN1 gene replacement. Early clinical trials of candidate therapeutics are now ongoing in SMA patients. Clinical trials in this disease present a unique set of challenges, including the development of meaningful outcome measures and disease biomarkers.
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Affiliation(s)
- Charlotte J Sumner
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
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48
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Baughan T, Shababi M, Coady TH, Dickson AM, Tullis GE, Lorson CL. Stimulating full-length SMN2 expression by delivering bifunctional RNAs via a viral vector. Mol Ther 2006; 14:54-62. [PMID: 16580882 DOI: 10.1016/j.ymthe.2006.01.012] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/21/2005] [Revised: 01/26/2006] [Accepted: 01/31/2006] [Indexed: 11/29/2022] Open
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is the leading genetic cause of infant mortality. SMA is caused by the loss of survival motor neuron-1 (SMN1). In humans, a nearly identical copy gene is present, called SMN2. SMN2 is retained in all SMA patients and encodes an identical protein compared to SMN1. However, a single silent nucleotide difference in SMN2 exon 7 results in the production of a spliced isoform (called SMNDelta7) that encodes a nonfunctional protein. The presence of SMN2 represents a unique therapeutic target since SMN2 has the capacity to encode a fully functional protein. Here we describe an in vivo delivery system for short bifunctional RNAs that modulate SMN2 splicing. Bifunctional RNAs derive their name from the presence of two domains: an antisense RNA sequence specific to a target RNA and an untethered RNA segment that serves as a binding platform for splicing factors. Plasmid-based and recombinant adeno-associated virus vectors were developed that expressed bifunctional RNAs that stimulated SMN2 exon 7 inclusion and full-length SMN protein in patient fibroblasts. These experiments provide a mechanism to modulate splicing from a variety of genetic contexts and demonstrate directly a novel therapeutic approach for SMA.
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Affiliation(s)
- Travis Baughan
- Department of Molecular Microbiology and Immunology, Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
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49
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Eggert C, Chari A, Laggerbauer B, Fischer U. Spinal muscular atrophy: the RNP connection. Trends Mol Med 2006; 12:113-21. [PMID: 16473550 DOI: 10.1016/j.molmed.2006.01.005] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/31/2005] [Revised: 12/22/2005] [Accepted: 01/27/2006] [Indexed: 02/01/2023]
Abstract
Degenerated motor neurons in the spinal cord are the pathological hallmark of spinal muscular atrophy (SMA). SMA is caused by mutations in the ubiquitously expressed survival motor neuron 1 (SMN1) gene, which lead to reduced levels of functional SMN protein. Many different functions have been assigned to SMN, including assembly of ribonucleoproteins (RNPs), splicing, transcription and axonal mRNA transport. Recently, tissue from SMA patients and animal models has been used to determine which function of SMN is affected in SMA patients. A surprising picture has emerged: the impaired assembly of RNP subunits of the spliceosome seems to be responsible for SMA pathogenesis. Here, we present a model of how this defect might cause motor-neuron degeneration and consider potential therapies.
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Affiliation(s)
- Christian Eggert
- Theodor Boveri Institute, Biocenter at the University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
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50
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Grzeschik SM, Ganta M, Prior TW, Heavlin WD, Wang CH. Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Ann Neurol 2005; 58:194-202. [PMID: 16049920 DOI: 10.1002/ana.20548] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
Spinal muscular atrophy (SMA) is a motor neuron disease caused by dysfunction of the survival motor neuron (SMN) gene. Human SMN gene is present in duplicated copies: SMN1 and SMN2. More than 95% of patients with SMA lack a functional SMN1 but retain at least one copy of SMN2. Unlike SMN1, SMN2 is primarily transcribed into truncated messenger RNA and produces low levels of SMN protein. We tested a therapeutic strategy by treating cultured lymphocytes from patients with SMA with hydroxyurea to modify SMN2 gene expression and to increase the production of SMN protein. Twenty lymphoblastoid cell lines (15 SMA and 5 control lines) were treated with hydroxyurea at 5 concentrations (0.5, 5, 50, 500, and 5,000 microg/ml) and 3 time points (24, 48, and 72 hours). SMN2 gene copy numbers were determined using real-time quantitative polymerase chain reaction. Hydroxyurea treatment resulted in a time-related and dose-dependent increase in the ratio of full-length to truncated SMN messenger RNA. SMN protein levels and intranuclear gems also were significantly increased in these hydroxyurea-treated cells. The SMN2 gene copy number correlated inversely with the SMA phenotypic severity. This study provides the first evidence for a therapeutic indication of hydroxyurea in SMA.
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Affiliation(s)
- Susanna M Grzeschik
- Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford University, Stanford, CA 94305-5235, USA
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