1
|
Romano R, Bucci C. Antisense therapy: a potential breakthrough in the treatment of neurodegenerative diseases. Neural Regen Res 2024; 19:1027-1035. [PMID: 37862205 PMCID: PMC10749614 DOI: 10.4103/1673-5374.385285] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/17/2023] [Revised: 06/13/2023] [Accepted: 07/21/2023] [Indexed: 10/22/2023] Open
Abstract
Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system. Currently, there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide. Therefore, it is necessary to find new therapeutic approaches, and antisense therapies offer this possibility, having the great advantage of not modifying cellular genome and potentially being safer. Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases. The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases, with a focus on those antisense therapies that have already received the approval of the U.S. Food and Drug Administration.
Collapse
Affiliation(s)
- Roberta Romano
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy
| | - Cecilia Bucci
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy
| |
Collapse
|
2
|
Jiao Y, Zhao J, Wang Z, Chen X, Cai H, Huang X, Sun P, Shen J, Song F, Xiong H, Dai Y, Chen W, Shen J. How do orphan disease patients live during the pandemic of Omicron variant? A nationwide survey of spinal muscular atrophy patients in China. Int J Infect Dis 2023; 134:187-194. [PMID: 37352912 DOI: 10.1016/j.ijid.2023.06.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/10/2023] [Revised: 05/16/2023] [Accepted: 06/17/2023] [Indexed: 06/25/2023] Open
Abstract
OBJECTIVES To investigate the challenges of patients with spinal muscular atrophy (SMA) during the Omicron variant COVID-19 pandemic. DESIGN A cross-sectional survey was conducted in China from January 02, 2023, to January 12, 2023, using a questionnaire that covered three aspects: (1) Demographic information; (2) SMA-related information; and (3) COVID-19-related information. We recruited patients with SMA from 33 provinces. The prevalence, course, and clinical manifestations of COVID-19 were calculated. The relationships between independent and outcome variables were investigated. RESULTS In total, 677 patients (male: 349; female: 328) were included in this study (average age = 11.40 years); 534 (78.88%) suffered from COVID-19. The most common symptoms were fever (95.51%), cough (57.87%), and sputum (49.44%). Of the infected patients, 91.57% recovered with at-home care, and 8.43% were hospitalized; 1.31% were admitted to the intensive care unit (ICU). A positive correlation was observed between the SMA severity and hospitalization rate. The ICU stay rate in patients with SMA type I was significantly higher than that in other SMA types. CONCLUSION This is the first large sample survey to timely reveal the living situation of patients with SMA during the COVID-19 pandemic's Omicron variant. Patients with SMA type I should be paid more attention in terms of hospitalization and ICU stay.
Collapse
Affiliation(s)
- Yang Jiao
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Junduo Zhao
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Zhen Wang
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Xin Chen
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Haoyu Cai
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Xu'an Huang
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Peiyu Sun
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Jiayi Shen
- University of International Business and Economics, Beijing, People's Republic of China
| | - Fang Song
- Capital Institute of Pediatrics, Beijing, People's Republic of China
| | - Hui Xiong
- Department of Pediatrics, Peking University First Hospital, Peking University, Beijing, People's Republic of China
| | - Yi Dai
- Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Weiyun Chen
- Department of Anesthesiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China
| | - Jianxiong Shen
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, People's Republic of China.
| |
Collapse
|
3
|
Ingle RG, Fang WJ. An Overview of the Stability and Delivery Challenges of Commercial Nucleic Acid Therapeutics. Pharmaceutics 2023; 15:pharmaceutics15041158. [PMID: 37111643 PMCID: PMC10143938 DOI: 10.3390/pharmaceutics15041158] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/20/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 04/29/2023] Open
Abstract
Nucleic acid (NA)-based biopharmaceuticals have emerged as promising therapeutic modalities. NA therapeutics are a diverse class of RNA and DNA and include antisense oligonucleotides, siRNA, miRNA, mRNA, small activating RNA, and gene therapies. Meanwhile, NA therapeutics have posed significant stability and delivery challenges and are expensive. This article discusses the challenges and opportunities for achieving stable formulations of NAs with novel drug delivery systems (DDSs). Here we review the current progress in the stability issues and the significance of novel DDSs associated with NA-based biopharmaceuticals, as well as mRNA vaccines. We also highlight the European Medicines Agency (EMA) and US Food and Drug Administration (FDA)-approved NA-based therapeutics with their formulation profiles. NA therapeutics could impact future markets if the remaining challenges and requirements are addressed. Regardless of the limited information available for NA therapeutics, reviewing and collating the relevant facts and figures generates a precious resource for formulation experts familiar with the NA therapeutics' stability profile, their delivery challenges, and regulatory acceptance.
Collapse
Affiliation(s)
- Rahul G Ingle
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310027, China
- Dr. Rajendra Gode College of Pharmacy, Amravati 444602, India
| | - Wei-Jie Fang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310027, China
| |
Collapse
|
4
|
Anwar S, Mir F, Yokota T. Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier-Based Delivery Strategies. Pharmaceutics 2023; 15:pharmaceutics15041130. [PMID: 37111616 PMCID: PMC10140998 DOI: 10.3390/pharmaceutics15041130] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/20/2023] [Revised: 03/28/2023] [Accepted: 03/28/2023] [Indexed: 04/29/2023] Open
Abstract
Oligonucleotide-based therapies are a promising approach for treating a wide range of hard-to-treat diseases, particularly genetic and rare diseases. These therapies involve the use of short synthetic sequences of DNA or RNA that can modulate gene expression or inhibit proteins through various mechanisms. Despite the potential of these therapies, a significant barrier to their widespread use is the difficulty in ensuring their uptake by target cells/tissues. Strategies to overcome this challenge include cell-penetrating peptide conjugation, chemical modification, nanoparticle formulation, and the use of endogenous vesicles, spherical nucleic acids, and smart material-based delivery vehicles. This article provides an overview of these strategies and their potential for the efficient delivery of oligonucleotide drugs, as well as the safety and toxicity considerations, regulatory requirements, and challenges in translating these therapies from the laboratory to the clinic.
Collapse
Affiliation(s)
- Saeed Anwar
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Farin Mir
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Toshifumi Yokota
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| |
Collapse
|
5
|
Nanomedicine based strategies for oligonucleotide traversion across the blood-brain barrier. J Control Release 2023; 354:554-571. [PMID: 36649742 DOI: 10.1016/j.jconrel.2023.01.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/06/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/19/2023]
Abstract
Neurological disorders are considered the most prominent cause of disability worldwide. The major hurdle in the management of neurological disorders is the existence of the blood-brain barrier (BBB), which hinders the entry of several therapeutic moieties. In recent years, oligonucleotides have gained tremendous attention for their target specificity, diminished dose and adverse effects, thereby halting disease progression. However, enzymatic degradation, rapid clearance, limited circulation and availability at the bio-active site, etc., limit its clinical translation. Nanomedicine has opened up a breadth of opportunities in the delivery of oligonucleotides across the BBB. This review addresses the pitfalls associated with oligonucleotide delivery in traversing the BBB via nanotherapeutics for the management of brain disorders. Regulatory perspectives pertaining to hastening the clinical translation of oligonucleotide-loaded nanocarriers for brain delivery have been highlighted.
Collapse
|
6
|
Djordjevic D, McFadyen A, Anderson JA. Ethical challenges and opportunities in the development and approval of novel therapeutics for rare diseases. THE JOURNAL OF MEDICINE ACCESS 2023; 7:27550834231177507. [PMID: 37323852 PMCID: PMC10262601 DOI: 10.1177/27550834231177507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 01/25/2023] [Accepted: 05/05/2023] [Indexed: 06/17/2023]
Abstract
The development of novel therapeutics for rare "orphan" diseases has brought a growing tension between the desire to accelerate access to these breakthrough therapies and the need to generate quality evidence regarding their safety and efficacy. Accelerating the pace of drug development and approval may facilitate the rapid delivery of benefits to patients and cost savings for research and development, which theoretically improves affordability of drugs for the health system. However, several ethical challenges arise with expedited approval, compassionate release of drugs, and subsequent study of drugs in "real-world" settings. In this article, we explore the changing landscape of drug approval and the ethical challenges expedited approval creates for patients, caregivers, clinicians, and institutions, and propose tangible strategies to maximize the benefits of "real-world" data acquisition while mitigating risks to patients, clinicians, and institutions.
Collapse
|
7
|
Carey KA, Farrar MA, Kasparian NA, Street DJ, De Abreu Lourenco R. Family, healthcare professional, and societal preferences for the treatment of infantile spinal muscular atrophy: A discrete choice experiment. Dev Med Child Neurol 2022; 64:753-761. [PMID: 34962299 DOI: 10.1111/dmcn.15135] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/13/2021] [Revised: 11/09/2021] [Accepted: 11/16/2021] [Indexed: 11/29/2022]
Abstract
AIM To understand the factors that most influence decision-making in the treatment of infantile spinal muscular atrophy (SMA). METHOD A discrete choice experiment was conducted among parents of people with SMA (parents), healthcare professionals (HCPs), and members of the Australian general population (GenPop). Respondents were asked to accept/reject treatment for an infant newly diagnosed with SMA in eight hypothetical scenarios, characterized by different combinations of the attributes of the treatment offered. The results were analyzed using probability analysis. RESULTS Completed responses were provided from 1113 individuals (1024 GenPop, 21 parents, 68 HCPs). Respondents were more likely to accept treatments that improved functioning and mobility. Treatments with higher costs, invasive delivery, and risks of adverse events were accepted less often. Cost most affected treatment choices by HCPs and GenPop, while change in mobility and mode of administration were most influential for parents. INTERPRETATION These results highlight the importance of understanding value for money and clinical impact in affecting treatment choice, which are crucial for effective planning of healthcare and the successful implementation of treatment programmes for SMA. What this paper adds Spinal muscular atrophy (SMA) treatments with a higher chance of improving functioning and mobility are preferred by the general population, parents, and healthcare professionals. Treatments with higher costs, invasive delivery, and risk of adverse events are less preferred. Willingness to pay for SMA treatments increases with impact on functioning.
Collapse
Affiliation(s)
- Kate A Carey
- School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, NSW, Australia.,Department of Neurology, Sydney Children's Hospital, Randwick, Sydney, NSW, Australia
| | - Michelle A Farrar
- School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, NSW, Australia.,Department of Neurology, Sydney Children's Hospital, Randwick, Sydney, NSW, Australia
| | - Nadine A Kasparian
- Cincinnati Children's Center for Heart Disease and Mental Health, Heart Institute and the Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Deborah J Street
- Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, NSW, Australia
| | - Richard De Abreu Lourenco
- Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, NSW, Australia
| |
Collapse
|
8
|
Blonda A, Barcina Lacosta T, Toumi M, Simoens S. Assessing the Value of Nusinersen for Spinal Muscular Atrophy: A Comparative Analysis of Reimbursement Submission and Appraisal in European Countries. Front Pharmacol 2022; 12:750742. [PMID: 35126102 PMCID: PMC8814578 DOI: 10.3389/fphar.2021.750742] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/31/2021] [Accepted: 09/30/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Nusinersen is an orphan drug intended for the treatment of spinal muscular atrophy (SMA), a severe genetic neuromuscular disorder. Considering the very high costs of orphan drugs and the expected market entry of cell and gene therapies, there is increased interest in the use of health technology assessment (HTA) for orphan drugs. This study explores the role of the economic evaluation and budget impact analysis on the reimbursement of nusinersen. Methods: Appraisal reports for nusinersen were retrieved from reimbursement and HTA agencies in Belgium, Canada, France, England and Wales, Germany, Italy, Ireland, Scotland, Sweden, the Netherlands, and the United States. Detailed information was extracted on the economic evaluation, the budget impact, the overall reimbursement decision, and the managed entry agreement (MEA). Costs were adjusted for inflation and currency. Results: Overall, the reports included limited data on budget impact, excluding information on the sources of data for cost and patient estimates. Only three jurisdictions reported on total budget impact, estimated between 30 and 40 million euros per year. For early-onset SMA, the incremental cost-effectiveness threshold (ICER) ranged from €464,891 to €6,399,097 per quality-adjusted life year (QALY) gained for nusinersen versus standard of care. For later-onset SMA, the ICER varied from €493,756 to €10,611,936 per QALY. Although none of the jurisdictions found nusinersen to be cost-effective, reimbursement was granted in each jurisdiction. Remarkably, only four reports included arguments in favor of reimbursement. However, the majority of the jurisdictions set up an MEA, which may have promoted a positive reimbursement decision. Conclusion: There is a need for more transparency on the appraisal process and conditions included in the MEA. Additionally, by considering all relevant criteria explicitly during the appraisal process, decision-makers are in a better position to justify their allocation of funds among the rising number of orphan drugs that are coming to the market in the near future.
Collapse
Affiliation(s)
- Alessandra Blonda
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | | | - Mondher Toumi
- Department of Public Health, Aix-Marseille Université, Marseille, France
| | - Steven Simoens
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| |
Collapse
|
9
|
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.
Collapse
Affiliation(s)
- Bijaylaxmi Behera
- Department of Neonatology, Chaitanya Hospital, Chandigarh 160044, India
| |
Collapse
|
10
|
Hiebeler M, Abicht A, Reilich P, Walter MC. Effect of Discontinuation of Nusinersen Treatment in Long-Standing SMA3. J Neuromuscul Dis 2021; 8:537-542. [PMID: 33682724 DOI: 10.3233/jnd-210644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Spinal muscular atrophy is an autosomal recessive neuromuscular disease leading to ongoing degeneration of anterior horn cells in the spinal cord. Nusinersen is the first approved treatment for the condition, an intrathecally administered antisense oligonucleotide. It modulates pre-RNA splicing of the SMN2 gene and increases full-length SMN protein expression, thereby increasing SMN protein levels. The benefit of Nusinersen for patients with spinal muscular atrophy type 3 (SMA3) has recently been shown in several real-world cohorts. OBJECTIVE We aim to elucidate not only the effect of therapy with Nusinersen, but the development of the disease course after discontinuation of treatment. To our knowledge, there are so far no reports on the effects of Nusinersen discontinuation. METHODS We report on a 45-year-old female patient with genetically confirmed SMA3 and a disease duration of 40 years prior to treatment onset. RESULTS The patient was non-ambulantory, best motor function at treatment onset was holding arms with support, reflected in MRC of 3/5 in upper limbs. After having received Nusinersen for 11 months without complications, the patient showed improvement in motor functions, as measured by hand grip measurement (HGS), Hammersmith Functional Rating Scale Expanded (HFMSE), and Revised Upper Limb Module (RULM). Due to worsening of a pre-existing anxiety disorder, treatment was discontinued after six injections. Sixteen months later, progression of the disease became evident with worsening of HFMSE and RULM scores, while hand strength remained stable. CONCLUSION Treatment with Nusinersen in SMA3 improves motor function in longstanding disease even in clinically advanced stages; however, after discontinuation of treatment, further progression mirroring the natural history of the disease is anticipated.
Collapse
Affiliation(s)
- Miriam Hiebeler
- Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Angela Abicht
- Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.,Medical Genetics Center - MGZ, Munich, Germany
| | - Peter Reilich
- Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Maggie C Walter
- Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany
| |
Collapse
|
11
|
Jalali A, Rothwell E, Botkin JR, Anderson RA, Butterfield RJ, Nelson RE. Cost-Effectiveness of Nusinersen and Universal Newborn Screening for Spinal Muscular Atrophy. J Pediatr 2020; 227:274-280.e2. [PMID: 32659229 PMCID: PMC7686158 DOI: 10.1016/j.jpeds.2020.07.033] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/08/2020] [Revised: 07/03/2020] [Accepted: 07/08/2020] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To evaluate the cost-effectiveness of nusinersen with and without universal newborn screening for infantile-onset spinal muscular atrophy (SMA). STUDY DESIGN A Markov model using data from clinical trials with US epidemiologic and cost data was developed. The primary interventions studied were nusinersen treatment in a screening setting, nusinersen treatment in a nonscreening setting, and standard care. Analysis was conducted from a societal perspective. RESULTS Compared with no screening and no treatment, the incremental cost-effectiveness ratio (ICER) for nusinersen with screening was $330 558 per event-free life year (LY) saved, whereas the ICER for nusinersen treatment without screening was $508 481 per event-free LY saved. For nusinersen with screening to be cost-effective at a willingness-to-pay (WTP) threshold of $50 000 per event-free LY saved, the price would need to be $23 361 per dose, less than one-fifth its current price of $125 000. Preliminary data from the NURTURE trial indicated an 85.7% improvement in expected LYs saved compared with our base results. In probabilistic sensitivity analysis, nusinersen and screening was a preferred strategy 93% of the time at a $500 000 WTP threshold. CONCLUSION Universal newborn screening for SMA provides improved economic value for payers and patients when nusinersen is available.
Collapse
Affiliation(s)
- Ali Jalali
- Department of Population Health Sciences, Weill Cornell Medical College, New York, NY.
| | - Erin Rothwell
- Department of Obstetrics and Gynecology, University of Utah School of Medicine
| | - Jeffrey R. Botkin
- Utah Center of Excellence in ELSI Research;,Department of Pediatrics, University of Utah School of Medicine
| | - Rebecca A. Anderson
- Utah Center of Excellence in ELSI Research;,Department of Pediatrics, University of Utah School of Medicine
| | | | - Richard E. Nelson
- IDEAS Center, Veterans Administration Salt Lake City Health Care System;,Division of Epidemiology, University of Utah School of Medicine
| |
Collapse
|
12
|
Le TK, Paris C, Khan KS, Robson F, Ng WL, Rocchi P. Nucleic Acid-Based Technologies Targeting Coronaviruses. Trends Biochem Sci 2020; 46:351-365. [PMID: 33309323 PMCID: PMC7691141 DOI: 10.1016/j.tibs.2020.11.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/11/2020] [Revised: 11/19/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently creating a global health emergency. This crisis is driving a worldwide effort to develop effective vaccines, prophylactics, and therapeutics. Nucleic acid (NA)-based treatments hold great potential to combat outbreaks of coronaviruses (CoVs) due to their rapid development, high target specificity, and the capacity to increase druggability. Here, we review key anti-CoV NA-based technologies, including antisense oligonucleotides (ASOs), siRNAs, RNA-targeting clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas), and mRNA vaccines, and discuss improved delivery methods and combination therapies with other antiviral drugs.
Collapse
Affiliation(s)
- Thi Khanh Le
- Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University U105, Institut Paoli-Calmettes Marseille, France; Department of Life Sciences, University of Science and Technology of Hanoi (USTH), Hanoi, Vietnam
| | - Clément Paris
- Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University U105, Institut Paoli-Calmettes Marseille, France
| | - Khadija Shahed Khan
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Fran Robson
- School of Biological Sciences, University of Bristol, Bristol, UK
| | - Wai-Lung Ng
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
| | - Palma Rocchi
- Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University U105, Institut Paoli-Calmettes Marseille, France.
| |
Collapse
|
13
|
Chua KP, Conti RM. Trends In Orphan Drug Spending And Out-Of-Pocket Spending Among US Children, 2013-18. Health Aff (Millwood) 2020; 39:1806-1811. [PMID: 33017253 DOI: 10.1377/hlthaff.2020.00595] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/05/2022]
Abstract
Among privately insured children, the proportion of inflation-adjusted total health care spending accounted for by orphan drugs increased from 4.0 percent to 6.6 percent between 2013 and 2018. This increase was largely driven by price growth. Mean annual out-of-pocket spending for orphan drugs rose from $486 to $866 and was higher for children than adults.
Collapse
Affiliation(s)
- Kao-Ping Chua
- Kao-Ping Chua is an assistant professor in the Department of Pediatrics and the Susan B. Meister Child Health Evaluation and Research Center at the University of Michigan Medical School, in Ann Arbor, Michigan
| | - Rena M Conti
- Rena M. Conti is an associate professor in the Department of Markets, Public Policy, and Law at the Questrom Boston University School of Business, in Boston, Massachusetts
| |
Collapse
|
14
|
Abstract
Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches - including chemical modification, bioconjugation and the use of nanocarriers - which aim to address the delivery challenge.
Collapse
|
15
|
Song JY, Kim HS, Park SJ, Lee J, Lee J. Nusinersen Administration in Spinal Muscular Atrophy Patients with Severe Scoliosis: Interlaminar Approaches at the Lumbar Level. ANNALS OF CHILD NEUROLOGY 2020. [DOI: 10.26815/acn.2020.00045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022] Open
|
16
|
“The Whole Game is Changing and You’ve Got Hope”: Australian Perspectives on Treatment Decision Making in Spinal Muscular Atrophy. PATIENT-PATIENT CENTERED OUTCOMES RESEARCH 2020; 13:389-400. [DOI: 10.1007/s40271-020-00415-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/28/2022]
|
17
|
Droege M, Sproule D, Arjunji R, Gauthier-Loiselle M, Cloutier M, Dabbous O. Economic burden of spinal muscular atrophy in the United States: a contemporary assessment. J Med Econ 2020; 23:70-79. [PMID: 31322019 DOI: 10.1080/13696998.2019.1646263] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022]
Abstract
Aims: To estimate healthcare resource utilization (HRU) and costs among patients with spinal muscular atrophy (SMA) type 1 (SMA1) in real-world practice, overall and among patients treated with nusinersen. As a secondary objective, HRU and costs were estimated among patients with other SMA types (i.e. 2, 3, or 4 combined), overall and among patients treated with nusinersen.Materials and methods: Patients with SMA were identified from the Symphony Health's Integrated Dataverse (IDV) open claims database (September 1, 2016-August 31, 2018) and were classified into four cohorts based on SMA type and nusinersen treatment (i.e. SMA1, SMA1 nusinersen, other SMA, and other SMA nusinersen cohorts). The index date was the date of the first SMA diagnosis after December 23, 2016 or, for nusinersen cohorts, the date of nusinersen initiation. The study period spanned from the index date to the earlier among the end of clinical activity or data availability.Results: Patients in the SMA1 (n = 349) and SMA1 nusinersen (n = 45) cohorts experienced an average of 59.4 and 56.6 days with medical visits per-patient-per-year (PPPY), respectively, including 14.1 and 4.6 inpatient days. Excluding nusinersen-related costs, total mean healthcare costs were $137,627 and $92,618 PPPY in the SMA1 and SMA1 nusinersen cohorts, respectively. Mean nusinersen-related costs were $191,909 per-patient-per-month (PPPM) for the first 3 months post-initiation (i.e. loading phase) and $36,882 PPPM thereafter (i.e. maintenance phase). HRU and costs were also substantial among patients in the other SMA (n = 5,728) and other SMA nusinersen (n = 404) cohorts, with an average of 44.5 and 63.7 days with medical visits PPPY and total mean healthcare costs (excluding nusinersen-related costs) of $49,175 and $76,371 PPPY, respectively.Limitations: The database may contain inaccuracies or omissions in diagnoses, procedures, or costs, and does not capture medical services outside of the IDV network.Conclusions: HRU and healthcare costs were substantial in patients with SMA, including in nusinersen-treated patients.
Collapse
|
18
|
Hoot NR. Nusinersen for Type 1 Spinal Muscular Atrophy: A Father's Perspective. Pediatrics 2019; 144:peds.2019-0226. [PMID: 31506303 DOI: 10.1542/peds.2019-0226] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Accepted: 04/22/2019] [Indexed: 11/24/2022] Open
Affiliation(s)
- Nathan R Hoot
- Department of Emergency Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas
| |
Collapse
|
19
|
Sequencing as a first-line methodology for cystic fibrosis carrier screening. Genet Med 2019; 21:2569-2576. [PMID: 31036917 PMCID: PMC6831513 DOI: 10.1038/s41436-019-0525-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/13/2019] [Accepted: 04/16/2019] [Indexed: 12/18/2022] Open
Abstract
Purpose Medical society guidelines recommend offering genotyping-based
cystic fibrosis (CF) carrier screening to pregnant women or women considering
pregnancy. We assessed the performance of sequencing-based CF screening relative
to genotyping, in terms of analytical validity, clinical validity, clinical
impact, and clinical utility. Methods Analytical validity was assessed using orthogonal confirmation and
reference samples. Clinical validity was evaluated using the CFTR2 database.
Clinical impact was assessed using ~100,000 screened patients. Three screening
strategies were compared: genotyping 23 guideline-recommended variants (“CF23”),
sequencing all coding bases in CFTR (“NGS”),
and sequencing with large copy-number variant (CNV) identification
(“NGS + CNV”). Clinical utility was determined via self-reported actions of
at-risk couples (ARCs). Results Analytical accuracy of NGS + CNV was 100% for SNVs, indels, and
CNVs; interpretive clinical specificity relative to CFTR2 was 99.5%. NGS + CNV
detected 58 ARCs, 18 of whom would have gone undetected with CF23 alone. Most
ARCs (89% screened preconceptionally, 56% prenatally) altered pregnancy
management, and no significant differences were observed between ARCs with or
without at least one non-CF23 variant. Conclusion Modern NGS and variant interpretation enable accurate
sequencing-based CF screening. Limiting screening to 23 variants does not
improve analytical validity, clinical validity, or clinical utility, but does
fail to detect approximately 30% (18/58) of ARCs.
Collapse
|
20
|
Gidaro T, Servais L. Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps. Dev Med Child Neurol 2019; 61:19-24. [PMID: 30221755 DOI: 10.1111/dmcn.14027] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Accepted: 07/25/2018] [Indexed: 01/08/2023]
Abstract
Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.
Collapse
Affiliation(s)
- Teresa Gidaro
- I-Motion - Pediatric Clinical Trials Department, Trousseau Hospital, Paris, France.,Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France
| | - Laurent Servais
- I-Motion - Pediatric Clinical Trials Department, Trousseau Hospital, Paris, France.,Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.,CHU de Liège, Centre de référence des maladies Neuromusculaires, Liège, Belgium
| |
Collapse
|
21
|
Abstract
By definition, congenital myopathy typically presents with skeletal muscle weakness and hypotonia at birth. Traditionally, congenital myopathy subtypes have been predominantly distinguished on the basis of the pathological hallmarks present on skeletal muscle biopsies. Many genes cause congenital myopathies when mutated, and a burst of new causative genes have been identified because of advances in gene sequencing technology. Recent discoveries include extending the disease phenotypes associated with previously identified genes and determining that genes formerly known to cause only dominant disease can also cause recessive disease. The more recently identified congenital myopathy genes account for only a small proportion of patients. Thus, the congenital myopathy genes remaining to be discovered are predicted to be extremely rare causes of disease, which greatly hampers their identification. Significant progress in the provision of molecular diagnoses brings important information and value to patients and their families, such as possible disease prognosis, better disease management, and informed reproductive choice, including carrier screening of parents. Additionally, from accurate genetic knowledge, rational treatment options can be hypothesised and subsequently evaluated
in vitro and in animal models. A wide range of potential congenital myopathy therapies have been investigated on the basis of improved understanding of disease pathomechanisms, and some therapies are in clinical trials. Although large hurdles remain, promise exists for translating treatment benefits from preclinical models to patients with congenital myopathy, including harnessing proven successes for other genetic diseases.
Collapse
Affiliation(s)
- Gianina Ravenscroft
- Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.,Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia
| | | | - Kristen J Nowak
- Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.,Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia.,School of Biological Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, QEII Medical Centre, Nedlands, WA, Australia.,Office of Population Health Genomics, Western Australian Department of Health, East Perth, WA, Australia
| | - Nigel G Laing
- Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.,Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, Australia.,Department of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia
| |
Collapse
|
22
|
Sansone VA, Albamonte E, Salmin F, Casiraghi J, Pirola A, Bettinelli M, Rao F, Mancini L, Tovaglieri N, Fedeli F, Stoia P, Heinen M, Cozzi V, Carraro E, Lunetta C, Di Bari A, Mercuri E. Intrathecal nusinersen treatment for SMA in a dedicated neuromuscular clinic: an example of multidisciplinary and integrated care. Neurol Sci 2018; 40:327-332. [PMID: 30430317 DOI: 10.1007/s10072-018-3622-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/09/2018] [Accepted: 10/24/2018] [Indexed: 11/29/2022]
Abstract
Nusinsersen is now available in Italy for all SMA types. We describe the experience with intrathecal treatment with nusinersen in 50 patients with SMA at the NEMO Center (NEuroMuscular Omniservice Clinical Center) in Milan, a neuromuscular patient-centered clinic hosted within Niguarda Hospital, a National Public General Hospital. Our results indicate that the pathway of care described outweighs the burden due to the repeated intrathecal injections. Irrespective of age and severity, the treatment is feasible, accessible, and replicable provided that there is a multidisciplinary team having experience and training in SMA.
Collapse
Affiliation(s)
- Valeria A Sansone
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy.
| | - Emilio Albamonte
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | - Francesca Salmin
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | - Jacopo Casiraghi
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | - Alice Pirola
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | - Massimo Bettinelli
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | - Fabrizio Rao
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | | | | | | | - Paolo Stoia
- Dept of Pediatrics, ASST Niguarda, Milan, Italy
| | | | | | - Elena Carraro
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | - Christian Lunetta
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | - Alessandra Di Bari
- Neurorehabilitation Unit, the NEMO Clinical Center in Milan, University of Milan, Milan, Italy
| | - Eugenio Mercuri
- Child Neurology Department, the NEMO Clinical Center, Policlinico Universitario "A. Gemelli", Rome, Italy
| | | |
Collapse
|
23
|
Missing Potential Conflict of Interest. JAMA Pediatr 2018; 172:891. [PMID: 30073265 DOI: 10.1001/jamapediatrics.2018.2493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/14/2022]
|
24
|
Prasad V. Inconsistent Reporting of Potential Conflicts of Interest. JAMA Pediatr 2018; 172:886. [PMID: 30073291 DOI: 10.1001/jamapediatrics.2018.2420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/14/2022]
Affiliation(s)
- Vinay Prasad
- Division of Hematology Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland.,Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland
| |
Collapse
|
25
|
Affiliation(s)
- Vinay Prasad
- Center for Health Care Ethics, Division of Hematology and Medical Oncology, Department of Preventive Medicine and Public Health, Knight Cancer Institute, Oregon Health and Science University, Portland
| |
Collapse
|
26
|
|