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Melocchi A, Schmittlein B, Sadhu S, Nayak S, Lares A, Uboldi M, Zema L, di Robilant BN, Feldman SA, Esensten JH. Automated manufacturing of cell therapies. J Control Release 2025; 381:113561. [PMID: 39993639 DOI: 10.1016/j.jconrel.2025.02.057] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 02/26/2025]
Abstract
Advanced therapy medicinal products (ATMPs), particularly genetically engineered cell-based therapies, are a major class of drugs with several high-profile Food and Drug Administration (FDA) approvals in the past decade. However, the high cost and limited production capacity of these drugs remain a barrier to access. These costs are primarily due to the complex manufacturing processes (often a single batch for a single patient), which increases personnel and facility expenses, and the challenges associated with tech-transfer from research and development stages to clinical-stage production. In order to scale up and scale out in a cost-effective way, automated solutions capable of multi-step manufacturing have been developed in academia and industry. The aim of the present article is to summarize the design approaches and key features of current multi-step automated systems for cell therapy manufacturing. For each system described in the literature, we will discuss different aspects in detail such as cell specificity, modularity, processing models, manufacturing locations, and integrated quality control. Our analysis highlights that developers need to balance competing needs in an environment where the biological, business, and technological factors are constantly evolving. Thus, designing engineering solutions that align with the pharmaceutical end-user is essential. Adopting a risk-based approach grounded in published data is the most effective strategy to evaluate existing and emerging automated systems.
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Affiliation(s)
- Alice Melocchi
- Sezione di Tecnologia e Legislazione Farmaceutiche "M. E. Sangalli", Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italy; Multiply Labs, San Francisco, CA, USA.
| | | | | | | | | | - Marco Uboldi
- Sezione di Tecnologia e Legislazione Farmaceutiche "M. E. Sangalli", Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italy
| | - Lucia Zema
- Sezione di Tecnologia e Legislazione Farmaceutiche "M. E. Sangalli", Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Milano, Italy
| | | | - Steven A Feldman
- Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Jonathan H Esensten
- Advanced Biotherapy Center (ABC), Sheba Medical Center, Tel Hashomer, Israel
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Rahnama M, Ghasemzadeh N, Latifi Z, Kheradmand F, Koukia FA, Khan S, Golchin A. Menstrual blood and endometrial mesenchymal stem/stromal cells: A frontier in regenerative medicine and cancer therapy. Eur J Pharmacol 2025; 1000:177726. [PMID: 40350020 DOI: 10.1016/j.ejphar.2025.177726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
The acquisition of suitable stem cell sources is a significant issue in regenerative medicine. There has been considerable interest in utilizing mesenchymal stem cells (MSCs) derived from endometrial and menstrual blood as a promising resource of MSCs, owing to their unique biochemical properties and prospective use in clinical therapies. This population of stem cells has distinct characteristics in terms of immunophenotype, proliferation rate, and differentiation capacity. A notable characteristic of these stem cells is their capacity to develop into mesodermal lineages, highlighting their regenerative capability. Moreover, the presence of certain surface markers facilitates the augmentation of clonogenic endometrial MSCs. Their distinctive characteristics, along with their swift multiplication ability, underscore their significant promise for therapeutic applicability in regenerative medicine and cell-based treatments. Current investigations are examining possible usage of diverse stem cell resources in the treatment of inflammatory diseases and perhaps intractable illnesses like Parkinson's disease, utilizing their immunomodulatory properties. This review aims to analyze stem cell-related research that has utilized endometrial and menstrual blood-derived MSCs (enMSCs and MenSCs) with a special focus on their clinical application. We will explore the existing evidence about the therapeutic potential for these stem cells across many medical diseases and address the obstacles and prospective trajectories in this domain. Additionally, we will study the unique properties of enMSCs and MenSCs that make them promising candidates for regenerative medicine.
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Affiliation(s)
- Maryam Rahnama
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Navid Ghasemzadeh
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Zeinab Latifi
- Department of Biochemistry, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Kheradmand
- Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Fariba Abbasi Koukia
- Department of Pathology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Sharun Khan
- Graduate Institute of Medicine, Yuan Ze University, Taoyuan 32003, Taiwan
| | - Ali Golchin
- Department of Applied Cell Sciences, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran; Independent Researcher, Urmia, Iran.
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Wang W, Song AR, Liu HW, Li YK. Enhancing the clinical translation of stem cell models by focusing on standardization and international regulatory cooperation. World J Stem Cells 2025; 17:102788. [PMID: 40308886 PMCID: PMC12038456 DOI: 10.4252/wjsc.v17.i4.102788] [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] [Scholar Register] [Received: 11/01/2024] [Revised: 02/12/2025] [Accepted: 03/10/2025] [Indexed: 04/23/2025] Open
Abstract
The article by Granjeiro et al provided a thorough review of the role of stem cell models in the development of advanced therapy medicinal products. It emphasized the potential of stem cell models to refine preclinical studies and align with regulatory requirements for clinical applications. This article introduced a new perspective on enhancing the transition of stem cell research into clinical practice, focusing on the importance of international regulatory harmonization and the need for standardization in stem cell-based therapies.
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Affiliation(s)
- Wei Wang
- Department of Traditional Chinese Medicine, Youyang People's Hospital, Chongqing 409800, China
| | - An-Ran Song
- Department of Traditional Chinese Medicine, Youyang People's Hospital, Chongqing 409800, China
| | - Hong-Wen Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yi-Kai Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
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Essink SCM, Zomerdijk IM, Straus SMJM, Gardarsdottir H, De Bruin ML. Risk Minimisation Measures of Advanced Therapy Medicinal Products Authorised in the EU Between 2009 and 2023: A Cross-Sectional Study. Drug Saf 2025:10.1007/s40264-025-01550-9. [PMID: 40208555 DOI: 10.1007/s40264-025-01550-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2025] [Indexed: 04/11/2025]
Abstract
INTRODUCTION Because of the novelty of advanced therapy medicinal products (ATMPs), pro-active risk management is needed post-authorisation; for example, through implementation of additional risk minimisation measures (aRMMs). OBJECTIVE We described which aRMMs were introduced at marketing authorisation (MA) for ATMPs authorised in the European Union (EU), and for what safety concerns. METHODS We included all ATMPs ever authorised in the EU until December 31, 2023. Data on safety concerns and aRMMs was collected from the European public assessment reports (EPARs) related to initial MA for each ATMP. Safety concerns were categorised using the Medical Dictionary for Regulatory Activities (MedDRA®) or context of use, where appropriate. RESULTS Of the 25 included ATMPs, most (n = 23, 92.0%) were authorised with aRMMs. Of these 23 ATMPs, all (100%) had educational material for healthcare professionals. Additionally, educational material for patients/caregivers was in place for 18 (78.3%) ATMPs and a controlled distribution or controlled access programme for 16 (69.6%). Safety concerns related to 'Long term effects' (n = 23, 92.0%), 'Injury, poisoning and procedural complications' (n = 22, 88.0%), and 'Use in special populations' (e.g., use in pregnancy) (n = 20, 80.0%) were common among all 25 ATMPs. ATMPs often had aRMMs introduced that addressed safety concerns related to 'Injury, poisoning and procedural complications' (n = 19/23; 82.6%), 'General disorders and administration site conditions' (n = 8, 34.8%), and/or 'Immune system disorders' (n = 8, 34.8%). CONCLUSION The majority of ATMPs were authorised with aRMMs. Whilst educational materials were most prevalent, controlled distribution or controlled access programmes were also commonly introduced. For many ATMPs, aRMMs addressed risks related to 'Injury, poisoning and procedural complications'.
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Affiliation(s)
- Sharon C M Essink
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
- Department of Pharmacovigilance, Medicines Evaluation Board, Utrecht, The Netherlands
| | - Inge M Zomerdijk
- Department of Pharmacovigilance, Medicines Evaluation Board, Utrecht, The Netherlands
| | - Sabine M J M Straus
- Department of Pharmacovigilance, Medicines Evaluation Board, Utrecht, The Netherlands
- Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Helga Gardarsdottir
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
- Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, The Netherlands
- Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland
| | - Marie L De Bruin
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
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Čechová Z, Kubátová J, Bártová A, Jamárik J, Samek J. Beyond Reimbursement Status: Availability of Advanced Therapy Medicinal Products Across the European Union. Ther Innov Regul Sci 2025:10.1007/s43441-025-00769-z. [PMID: 40208421 DOI: 10.1007/s43441-025-00769-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/28/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND Advanced Therapy Medicinal Products (ATMPs) represent an innovative therapeutic approach with the potential to impact the treatment of rare diseases significantly. Although authorised centrally in the European Union, their market launch differs across Member States (MS). This study aimed to describe the ATMP market availability in MS and explore potential influencing factors, providing insights into specific barriers beyond pricing and reimbursement policies. METHODS ATMP availability was defined as the product launch in each MS. Data was collected through open governmental sources, databases, and communication with national competent authorities. Spearman's correlation coefficients were calculated to examine the relationship between ATMP availability and their characteristics (time since granting marketing authorisation, target patient population size, and cost). RESULTS We collected the availability data on 18 ATMPs from 23 EU MS. Market uptake varied significantly, with Germany (89%), France and Italy (61%) leading. Estonia and Latvia confirmed that no ATMP has been launched on their markets yet. Six ATMPs were available in more than one-third of the analysed MS. No significant correlation was observed between ATMP availability and analysed product characteristics except for time dependency for CAR T-cell therapies. CONCLUSION Beyond pricing and reimbursement processes, the ATMP commercialisation in particular MS is influenced by the marketing authorisation holder's decision and capacity. ATMPs face product-specific challenges in achieving EU-wide availability, including complex manufacturing, distribution, and administration processes. To increase the accessibility of innovative ATMP-based treatments, implementing the cross-border access framework or individual ATMP production under the hospital exemption is essential, especially in underserved MS.
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Affiliation(s)
- Zora Čechová
- Centre of Excellence CREATIC, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 62500, Czech Republic.
| | - Jana Kubátová
- Centre of Excellence CREATIC, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 62500, Czech Republic
| | - Adéla Bártová
- Centre of Excellence CREATIC, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 62500, Czech Republic
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jakub Jamárik
- Centre of Excellence CREATIC, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 62500, Czech Republic
| | - Jiří Samek
- Centre of Excellence CREATIC, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 62500, Czech Republic
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Brilliant CD, Finlay AY, Salek SM, Shah R, Bacon E, Laing H. Validation of the FROM-16 in family members of patients receiving advanced therapy medicinal product (ATMP). Qual Life Res 2025; 34:949-962. [PMID: 39862357 PMCID: PMC11982087 DOI: 10.1007/s11136-024-03880-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2024] [Indexed: 01/27/2025]
Abstract
PURPOSE Outcome-based pricing models which consider domains of value not previously considered in healthcare, such as societal outcomes, are of increasing interest for healthcare systems. Societal outcomes can include family-reported outcome measures (FROMs), which measure the impact of disease upon the patient's family members. The FROM-16 is a generic and easy-to-use family quality of life tool, but it has never been used in the context of patients undergoing advanced therapy medicinal product (ATMP) treatment. The use of potentially curative ATMPs is limited due their high cost and the low number of eligible patients. Using the FROM-16 to collect the impact on family of disease and treatment in ATMP patients may demonstrate additional value created by an ATMP intervention and strengthen the case for its use. METHODS This feasibility study aimed to test the validity of the FROM-16 in family members of ATMP patients as a prelude for its use in ATMP value estimation. Patients and family members (n = 24) were recruited from ATMP treatment centres in England and Wales. Family members completed the FROM-16 and were invited to a short debriefing interview. RESULTS The FROM-16 showed high validity demonstrated by strong internal consistency (Cronbach's alpha = 0.917) and intraclass correlation (0.803, 95%). Interviews identified that whilst the FROM-16 covered most areas of quality-of-life impact experienced by the participants, some explained that they also experienced other impacts upon their personal health and future outlook. CONCLUSION This feasibility study provides evidence that the FROM-16 could be used as part of a structured systematic approach to measure family quality of life impact in ATMP patients.
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Affiliation(s)
- Charles D Brilliant
- Value-based Health & Care Academy, School of Management, Swansea University, Swansea, SA1 8EN, UK
| | - Andrew Y Finlay
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
| | - Sam M Salek
- Public Health & Patient Safety Research Group, School of Life & Medical Sciences, University of Hertfordshire, Hatfield, AL10 9AB, UK
- Institute of Medicines Development, Paddock End House, Bucks, SL9 8BL, UK
| | - Rubina Shah
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
| | - Emily Bacon
- Value-based Health & Care Academy, School of Management, Swansea University, Swansea, SA1 8EN, UK.
| | - Hamish Laing
- Value-based Health & Care Academy, School of Management, Swansea University, Swansea, SA1 8EN, UK
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Cosma S, Cosma S, Pennetta D, Rimo G. Overcoming the "valleys of death" in advanced therapies: The role of finance. Soc Sci Med 2025; 366:117639. [PMID: 39705775 DOI: 10.1016/j.socscimed.2024.117639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/28/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
Advanced therapies are the frontier of medical research and have a relevant therapeutic potential and a profound social value. Despite this, their funding is hindered by many heterogeneous factors that obstruct their translation and survival on the market, even when approved and effective. Using an extensive bibliometric and systematic review of 174 articles published between 2001 and 2023, this study aims to identify the factors hindering the financing of advanced therapies and suggest future research lines to overcome the biomedical and economic "valleys of death". This study is the first review focused on advanced therapies from a financial perspective, and it contributes to advancing scientific knowledge in several ways. First, it highlights that finance academics paid little attention to the topic and most of their contributions are now outdated; therefore, there is the need to explore the new opportunities and solutions offered by financial innovation and the application of new technologies to financial activity. Second, it asks for an interdisciplinary approach to exploring advanced therapies' barriers from a holistic and process perspective and exploiting the social value generated by the development of innovative therapies. Finally, it analyzes the obstacles and value destroyed by the absence of an organic and coordinated process of public intervention, underscoring the imperative for further research to explore new public-private financial models and risk-sharing schemes and extend evaluation models by integrating financial and social value logic.
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Affiliation(s)
- Simona Cosma
- Department of Management, University of Bologna, Via Capo di Lucca, 34, 40126, Bologna, BO, Italy.
| | - Stefano Cosma
- Marco Biagi Department of Economics, University of Modena and Reggio Emilia, Via Jacopo Berengario, 51, 41121, Modena, MO, Italy.
| | - Daniela Pennetta
- Marco Biagi Department of Economics, University of Modena and Reggio Emilia, Via Jacopo Berengario, 51, 41121, Modena, MO, Italy.
| | - Giuseppe Rimo
- Department of Economics, University of Salento, Via Lecce-Monteroni, 73047, Monteroni di Lecce, LE, Italy.
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Shi J, Chen X, Hu H, Ung COL. The role of hospital pharmacists in supporting the appropriate and safe use of CGT/ATMPs: a scoping review of current insights. BMC Health Serv Res 2025; 25:52. [PMID: 39789612 PMCID: PMC11721208 DOI: 10.1186/s12913-024-12026-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 11/28/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND The role of hospital pharmacists in managing cell and gene therapy (CGT) and advanced therapy medicinal products (ATMPs) is gradually being recognized but the evidence about impact of their role has not been systematically reported. OBJECTIVE This study was aimed to summarize the professional services provided by hospital pharmacists on managing CGT/ATMPs and the evidence about the effects on patient care, as well as to identify the perceptions about pharmacists assuming a role that supports the appropriate and safe use of CGT/ATMPs. METHODS Literature from 4 electronic databases (PubMed, ScienceDirect, Web of Science, Scopus) were searched following PRISMA checklist to yield publications on the interventions provided by hospital pharmacists in the management of CGT/ATMPs dated since 1 January 2013 till 30 April 2023. RESULTS Thirty-four publications were included in this review. Eight studies involving hospital pharmacists participating in interventions for 1,012 hematopoietic stem cell transplant (HSCT) patients from 8 hospitals in 5 countries were identified. Common pharmacist-led interventions centered on medicine administration, prescribing, and monitoring of medicines use, resulting in significant improvement in patient adherence, satisfaction and knowledge. Of 26 studies, the perspectives assuming their roles in CGT/ATMPs management were categorized when patients receiving ATMPs (n = 2), HSCT and cellular-based therapy (n = 12), gene therapy (n = 6), and the chimeric antigen receptor (CAR) T-cell therapy (n = 6), mainly covering procurement, influences on prescribing, preparation and delivery, administration, monitoring of medicines use, human resources, training and development. The anticipated impact was primarily intended to promote pharmacy practice, multidisciplinary collaboration and improve patient clinical outcomes. CONCLUSION Leveraging the role of hospital pharmacists in multidisciplinary healthcare teams to develop a coordinated approach that supports pharmacy practice will better meet the management of CGT/ATMPs. For hospital pharmacists to step up their role in the multidisciplinary healthcare team, advancing their skillset in terms of clinical practice standards and medication management is essential.
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Affiliation(s)
- Junnan Shi
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Xianwen Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Hao Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
- Centre for Pharmaceutical Regulatory Sciences, University of Macau, Macao SAR, China
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Carolina Oi Lam Ung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.
- Centre for Pharmaceutical Regulatory Sciences, University of Macau, Macao SAR, China.
- Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macao SAR, China.
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Sharma Y, Ghatak S, Sen CK, Mohanty S. Emerging technologies in regenerative medicine: The future of wound care and therapy. J Mol Med (Berl) 2024; 102:1425-1450. [PMID: 39358606 DOI: 10.1007/s00109-024-02493-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 09/10/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
Wound healing, an intricate biological process, comprises orderly phases of simple biological processed including hemostasis, inflammation, angiogenesis, cell proliferation, and ECM remodeling. The regulation of the shift in these phases can be influenced by systemic or environmental conditions. Any untimely transitions between these phases can lead to chronic wounds and scarring, imposing a significant socio-economic burden on patients. Current treatment modalities are largely supportive in nature and primarily involve the prevention of infection and controlling inflammation. This often results in delayed healing and wound complications. Recent strides in regenerative medicine and tissue engineering offer innovative and patient-specific solutions. Mesenchymal stem cells (MSCs) and their secretome have gained specific prominence in this regard. Additionally, technologies like tissue nano-transfection enable in situ gene editing, a need-specific approach without the requirement of complex laboratory procedures. Innovating approaches like 3D bioprinting and ECM bioscaffolds also hold the potential to address wounds at the molecular and cellular levels. These regenerative approaches target common healing obstacles, such as hyper-inflammation thereby promoting self-recovery through crucial signaling pathway stimulation. The rationale of this review is to examine the benefits and limitations of both current and emerging technologies in wound care and to offer insights into potential advancements in the field. The shift towards such patient-centric therapies reflects a paradigmatic change in wound care strategies.
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Affiliation(s)
- Yashvi Sharma
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, Delhi, 110029, India
| | - Subhadip Ghatak
- Indiana Center for Regenerative Medicine and Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- McGowan Institute of Regenerative Medicine, Department of Surgery, University of Pittsburgh, 419 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA, 15219, USA
| | - Chandan K Sen
- Indiana Center for Regenerative Medicine and Engineering, Indiana University Health Comprehensive Wound Center, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- McGowan Institute of Regenerative Medicine, Department of Surgery, University of Pittsburgh, 419 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA, 15219, USA.
| | - Sujata Mohanty
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, Delhi, 110029, India.
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Granjeiro JM, Borchio PGDM, Ribeiro IPB, Paiva KBS. Bioengineering breakthroughs: The impact of stem cell models on advanced therapy medicinal product development. World J Stem Cells 2024; 16:860-872. [PMID: 39493828 PMCID: PMC11525646 DOI: 10.4252/wjsc.v16.i10.860] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/22/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
The burgeoning field of bioengineering has witnessed significant strides due to the advent of stem cell models, particularly in their application in advanced therapy medicinal products (ATMPs). In this review, we examine the multifaceted impact of these developments, emphasizing the potential of stem cell models to enhance the sophistication of ATMPs and to offer alternatives to animal testing. Stem cell-derived tissues are particularly promising because they can reshape the preclinical landscape by providing more physiologically relevant and ethically sound platforms for drug screening and disease modelling. We also discuss the critical challenges of reproducibility and accuracy in measurements to ensure the integrity and utility of stem cell models in research and application. Moreover, this review highlights the imperative of stem cell models to align with regulatory standards, ensuring using stem cells in ATMPs translates into safe and effective clinical therapies. With regulatory approval serving as a gateway to clinical adoption, the collaborative efforts between scientists and regulators are vital for the progression of stem cell applications from bench to bedside. We advocate for a balanced approach that nurtures innovation within the framework of rigorous validation and regulatory compliance, ensuring that stem cell-base solutions are maximized to promote public trust and patient health in ATMPs.
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Affiliation(s)
- José Mauro Granjeiro
- Division of Biological Metrology, The National Institute of Metrology, Quality, and Technology, Duque de Caxias 25250020, Rio de Janeiro, Brazil.
| | | | - Icaro Paschoal Brito Ribeiro
- Laboratory of Extracellular Matrix Biology and Cellular Interaction, Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508000, São Paulo, Brazil
| | - Katiucia Batista Silva Paiva
- Laboratory of Extracellular Matrix Biology and Cellular Interaction, Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508000, São Paulo, Brazil
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Cai Y, Sui L, Wang J, Qian W, Peng Y, Gong L, Wu W, Gao Y. Post-marketing surveillance framework of cell and gene therapy products in the European Union, the United States, Japan, South Korea and China: a comparative study. BMC Med 2024; 22:421. [PMID: 39334246 PMCID: PMC11438358 DOI: 10.1186/s12916-024-03637-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Cell and gene therapy products (CGTPs) often receive accelerated approvals, lacking comprehensive long-term safety and efficacy data, which can raise significant safety concerns. This research aims to study the post-marketing surveillance (PMS) of CGTPs in the European Union (EU), the United States (US), Japan, South Korea, and China, to offer insights for the development of a secure and standardized post-marketing regulatory framework for CGTPs. METHODS Related regulations and the implementation effect of PMS for approved CGTPs were studied searching PubMed, CNKI, and the official websites of the European Medicines Agency, the US Food and Drug Administration, Japan's Pharmaceuticals and Medical Device Agency, South Korea's Ministry of Food and Drug Safety, and the National Medical Products Administration of China. RESULTS Compared to those in China, the guidelines of PMS for CGTPs in the EU, the US, Japan, and South Korea was more comprehensive. Notably, the EU had dedicated regulations and supporting guidelines of PMS. Of the 26 CGTPs approved in the EU, 88% were under additional monitoring, 38% received conditional marketing authorization, and 12% were authorized under exceptional circumstances, with 77% designated as orphan drugs. The US had released 34 guidelines specifically for CGTPs which, forming the foundation of post-marketing risk management. Among the 27 CGTPs approved in the US, 22% were required to perform risk evaluation and mitigation strategies, 37% added black box warnings in the package inserts, 63% mandated to post-marketing requirements, and 15% subject to post-marketing commitments. In Japan, stringent supervision measures encompassing all-case surveillance (79%) and re-examination (53%) were applied to the 19 approved CGTPs, with 21% approved through conditional and time-limited approval. The PMS for CGTPs in South Korea, mainly included PSUR, re-examination, and re-evaluation. China had introduced several relevant regulations, which consisted of general statements and lacked detailed guidance. CONCLUSIONS This study demonstrates that the regulatory policies of PMS for CGTPs in the EU, the US, Japan, and South Korea were comprehensive. The implementation of PMS for CGTPs in the EU, the US, and Japan was well developed. This knowledge holds valuable insights for China's future learning and development in this field.
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Affiliation(s)
- Yuxin Cai
- Department of Clinical Pharmacy and Regulatory Science, School of Pharmacy, Fudan University, Shanghai, 201206, China
| | - Lijuan Sui
- Department of Clinical Pharmacy and Regulatory Science, School of Pharmacy, Fudan University, Shanghai, 201206, China
| | - Jingjing Wang
- Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200001, China
| | - Weilin Qian
- Department of Clinical Pharmacy and Regulatory Science, School of Pharmacy, Fudan University, Shanghai, 201206, China
| | - Yeheng Peng
- Department of Clinical Pharmacy and Regulatory Science, School of Pharmacy, Fudan University, Shanghai, 201206, China
| | - Luyao Gong
- Department of Clinical Pharmacy and Regulatory Science, School of Pharmacy, Fudan University, Shanghai, 201206, China
| | - Weijia Wu
- Center for Health Policy Studies, Zhejiang University School of Public Health, Hangzhou, 310058, China
| | - Yuan Gao
- Department of Clinical Pharmacy and Regulatory Science, School of Pharmacy, Fudan University, Shanghai, 201206, China.
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12
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Shi J, Chen X, Hu H, Ung COL. The evolving regulatory system of advanced therapy medicinal products in China: a documentary analysis using the World Health Organization Global Benchmarking Tool standards. Cytotherapy 2024; 26:954-966. [PMID: 38739075 DOI: 10.1016/j.jcyt.2024.04.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 04/12/2024] [Accepted: 04/24/2024] [Indexed: 05/14/2024]
Abstract
Advanced therapy medicinal products (ATMPs) are rapidly evolving to offer new treatment options. The scientific, technical, and clinical complexities subject drug regulatory authorizes to regulatory challenges. To advance the regulatory capacity for ATMPs, the National Medical Products Administration in China made changes to the drug regulatory system and developed regulatory science with the goal of addressing patient needs and encouraging innovation. This study aimed to systematically identify the regulatory evidence on ATMPs in China under the guidance of an overarching framework from the World Health Organization Global Benchmarking Tool. It was found that China's administrative authorities at all levels have issued a number of policy documents to promote the development of ATMPs, covering biopharmaceutical products research and development (n = 14), biopharmaceutical industry development (n = 9), high-quality development of medical institutions (n = 1), specific development plans/projects (n = 6) and specific regional development (n = 4). The legal and regulatory framework of ATMPs in China has been established and is subject to continuous adjustment in various aspects including regulations (n = 3), departmental rules or administrative normative documents (n = 22), and technical guidance (n = 15). As the regulatory reform continues, the drug review processes have been revised, and various technical standards have been launched, which aim to establish a regulatory approach that oversees the full life-cycle development of ATMPs in the country. The limited number of investigational new drug applications and approved ATMPs suggests a lag remains between the translation of advanced therapeutic technologies into clinically available medical products. To accelerate the translational research of ATMP in countries such as China, developing and adopting real-world evidence generated from clinical use in designated healthcare facilities to support scientific decision-making in ATMP regulation is warranted. The enhancement of regulatory capacity building and multi-stakeholder collaborations should also be encouraged to facilitate the timely evaluation of promising ATMPs to meet more patient needs.
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Affiliation(s)
- Junnan Shi
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, China
| | - Xianwen Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, China
| | - Hao Hu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, China; Centre for Pharmaceutical Regulatory Sciences, University of Macau, Taipa, Macao SAR, China; Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Carolina Oi Lam Ung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, China; Centre for Pharmaceutical Regulatory Sciences, University of Macau, Taipa, Macao SAR, China; Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China.
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13
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Godoi MM, Reis EM, Koepp J, Ferreira J. Perspective from developers: Tissue-engineered products for skin wound healing. Int J Pharm 2024; 660:124319. [PMID: 38866084 DOI: 10.1016/j.ijpharm.2024.124319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/24/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024]
Abstract
Tissue-engineered products (TEPs) are at the forefront of developmental medicines, precisely where monoclonal antibodies and recombinant cytokines were 30 years ago. TEPs development for treating skin wounds has become a fast-growing field as it offers the potential to find novel therapeutic approaches for treating pathologies that currently have limited or no effective alternatives. This review aims to provide the reader with the process of translating an idea from the laboratory bench to clinical practice, specifically in the context of TEPs designing for skin wound healing. It encompasses historical perspectives, approved therapies, and offers a distinctive insight into the regulatory framework in Brazil. We explore the essential guidelines for quality testing, and nonclinical proof-of-concept considering the Brazilian Network of Experts in Advanced Therapies (RENETA) and International Standards and Guidelines (ICH e ISO). Adopting a multifaceted approach, our discussion incorporates scientific and industrial perspectives, addressing quality, biosafety, non-clinical viability, clinical trial and real-word data for pharmacovigilance demands. This comprehensive analysis presents a panoramic view of the development of skin TEPs, offering insights into the evolving landscape of this dynamic and promising field.
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Affiliation(s)
- Manuella Machado Godoi
- Graduate Program in Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina- UFSC, Florianópolis, SC, Brazil.
| | - Emily Marques Reis
- Department of Chemical and Food Engineering, Federal University of Santa Catarina- UFSC, Florianópolis, SC, Brazil; Biocelltis Biotecnologia, Florianópolis, SC, Brazil
| | - Janice Koepp
- Biocelltis Biotecnologia, Florianópolis, SC, Brazil
| | - Juliano Ferreira
- Graduate Program in Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina- UFSC, Florianópolis, SC, Brazil.
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14
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Horan A, Warreth S, Hervig T, Waters A. The expanding role of blood and tissue establishments in the development of advanced therapy medicinal products. Cytotherapy 2024; 26:524-530. [PMID: 38441513 DOI: 10.1016/j.jcyt.2024.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/13/2024] [Accepted: 02/13/2024] [Indexed: 05/04/2024]
Abstract
BACKGROUND AIMS The relationship between blood establishments and advanced cellular therapies is evident in several European countries, with some involved in research and development and/or in manufacturing. The aim of the present study was to understand the advanced therapy medicinal product (ATMP) infrastructural, regulatory and logistic requirements needed for the Irish Blood Transfusion Service to support advanced therapeutics in Ireland. METHODS An online survey consisting of 13 questions was distributed in a targeted manner to the identified ATMP stakeholders in Ireland, namely those working in industry, health care, regulatory agencies or education. Subject matter experts in the field were approached and interviewed to gain further insight into the relationship between blood and tissue establishments (BTEs) and ATMPs, to explore the advantages these institutions have in development and to highlight potential challenges for implementation. RESULTS In total, 84.9% of survey respondents stated that BTEs have a role in the development of advanced therapeutics. Key BTE services identified as applicable to the ATMP sector from both surveys and interviews include the provision of starting materials for research and manufacturing, donor management, use of existing quality and traceability frameworks, product logistic strategies and Good Manufacturing Practice. Challenges for BTE expansion into the sector currently include high costs associated with ATMPs, lack of expertise in these therapies, limited therapeutic populations and no national ATMP strategic plan for Ireland. CONCLUSIONS Blood establishments have services and expertise that can be extended into the advanced therapy sector. The existing knowledge and skill base of BTEs in Ireland should be leveraged to accelerate the development of ATMP strategies for industry and healthcare.
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Affiliation(s)
- Aisling Horan
- Irish Blood Transfusion Service, National Blood Centre, Dublin, Ireland
| | - Shada Warreth
- School of Chemical and Pharmaceutical Sciences, Technological University Dublin, Dublin, Ireland; National Institute for Bioprocessing Research and Training (NIBRT), Co., Dublin, Ireland
| | - Tor Hervig
- Irish Blood Transfusion Service, National Blood Centre, Dublin, Ireland; School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Allison Waters
- Irish Blood Transfusion Service, National Blood Centre, Dublin, Ireland; UCD School of Public Health, Physiotherapy and Social Science, University College Dublin, Dublin, Ireland.
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15
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Kuchemüller KB, Pörtner R, Möller J. Implementation of mDoE-methods to a microcarrier-based expansion processes for mesenchymal stem cells. Biotechnol Prog 2024; 40:e3429. [PMID: 38334218 DOI: 10.1002/btpr.3429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 01/01/2024] [Accepted: 01/03/2024] [Indexed: 02/10/2024]
Abstract
The need for advanced therapy medicinal products (ATMPs) has gained increased attention in recent years. In this respect, a well-designed cell expansion process is needed to efficiently manufacture the required number of cells with the desired product quality. This step is challenging due to the biological complexity of the respective primary cell (e.g., mesenchymal stem cells (MSC)) and the usage of microcarrier-based expansion systems. One accelerating approach for process design is model-assisted Design of Experiments (mDoE) combining mathematical process models and statistical tools. In this study, the mDoE workflow was used for the development of an expansion processes with human immortalized mesenchymal stem cells (hMSC-TERT) and the aim of maximizing cell yield assuming only a limited amount of prior knowledge at a very early stage of development. First, suitable microcarriers for expansion in shake flasks were screened and the differentiation of the cells was proven. Second, initial experiments were performed to generate prior knowledge, which was then used to set up the mathematical model and to estimate the model parameters. Finally, the mDoE was used to determine and evaluate the design space to be performed experimentally. Overall, a cell expansion process using microcarriers in a shake flask culture was successfully implemented and a significant increase in cell yield (up to 6,2-fold) was achieved compared to literature.
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Affiliation(s)
- Kim B Kuchemüller
- Institute of Bioprocess and Biosystems Engineering, Hamburg University of Technology, Hamburg, Germany
| | - Ralf Pörtner
- Institute of Bioprocess and Biosystems Engineering, Hamburg University of Technology, Hamburg, Germany
| | - Johannes Möller
- Institute of Bioprocess and Biosystems Engineering, Hamburg University of Technology, Hamburg, Germany
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16
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Azimi-Alamouty M, Habibi MA, Ebrahimi Sadrabadi A, Jamalpoor Z. An in situ forming gelatin-based hydrogel loaded with soluble amniotic membrane promotes full-thickness wound regeneration in rats. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:1005-1014. [PMID: 38911243 PMCID: PMC11193504 DOI: 10.22038/ijbms.2024.74290.16140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 11/11/2023] [Indexed: 06/25/2024]
Abstract
Objectives Early effective treatment and appropriate coverage are vital for full-thickness wounds. Amnion membrane-derived products have recently emerged in tissue engineering. However, the optimal concentration, carrier for controlled release, and handling have remained challenges. This study aims to develop and optimize an in situ forming, amniotic-based hydrogel for wound healing. Materials and Methods Here, a composite matrix was fabricated with gelatin hydrogel modified with methacrylate functional group conjugated (GelMA) and keratose (wt.1%), loaded with mesenchymal stem cells (MSCs, 1×105 cell/ml) and optimized soluble amniotic membrane (SAM, 0.5 mg/ml). The physicochemical properties of the final subject were evaluated in vitro and in vivo environments. Results The results of the in vitro assay demonstrated that conjugation of the methacryloyl group with gelatin resulted in the formation of GelMA hydrogel (26.7±1.2 kPa) with higher mechanical stability. Modification of GelMA with a glycosaminoglycan sulfate (Keratose) increased controlled delivery of SAM (47.3% vs. 84.3%). Metabolic activity (93%) and proliferation (21.2 ± 1.5 µg/ml) of MSCs encapsulated in hydrogel improved by incorporation of SAM (0.5 mg/ml). Furthermore, the migration of fibroblasts was facilitated in the scratched assay by SAM (0.5 mg/ml)/MSCs (1×105 cell/ml) conditioned medium. The GelMA hydrogel groupes revealed regeneration of full-thickness skin defects in rats after 3 weeks due to the high angiogenesis (6.3 ± 0.3), cell migration, and epithelialization. Conclusion The results indicated in situ forming and tunable GelMA hydrogels containing SAM and MSCs could be used as efficient substrates for full-thickness wound regeneration.
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Affiliation(s)
- Mohammad Azimi-Alamouty
- Trauma Research Center, Aja University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering, Faculty of Basic Sciences and Advanced Technologies in Medicine, Royan Institute, ACECR, Tehran, Iran
| | - Mohammad amin Habibi
- Iranian Tissue Bank and Research Center, Gene, Cell and Tissue Institute, Tehran university of Medical Sciences, Tehran, Iran
| | - Amin Ebrahimi Sadrabadi
- Department of Tissue Engineering, Faculty of Basic Sciences and Advanced Technologies in Medicine, Royan Institute, ACECR, Tehran, Iran
| | - Zahra Jamalpoor
- Trauma Research Center, Aja University of Medical Sciences, Tehran, Iran
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17
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Pavyde E, Usas A, Pockevicius A, Maciulaitis R. Muscle-Derived Stem/Progenitor Cells Ameliorate Acute Kidney Injury in Rats through the Anti-Apoptotic Pathway and Demonstrate Comparable Effects to Bone Marrow Mesenchymal Stem Cells. MEDICINA (KAUNAS, LITHUANIA) 2023; 60:63. [PMID: 38256324 PMCID: PMC10821316 DOI: 10.3390/medicina60010063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/19/2023] [Accepted: 12/26/2023] [Indexed: 01/24/2024]
Abstract
Background and Objectives: To date, the therapeutic potential of skeletal muscle-derived stem/progenitor cells (MDSPCs) for acute kidney injury (AKI) has only been evaluated by our research group. We aimed to compare MDSPCs with bone marrow mesenchymal stem cells (BM-MSCs) and evaluate their feasibility for the treatment of AKI. Materials and Methods: Rats were randomly assigned to four study groups: control, GM (gentamicin) group, GM+MDSPCs, and GM+BM-MSCs. AKI was induced by gentamicin (80 mg/kg/day; i.p.) for 7 consecutive days. MDSPCs and BM-MSCs were injected 24 h after the last gentamicin injection. Kidney parameters were determined on days 0, 8, 14, 21, and 35. Results: MDSPCs and BM-MSCs accelerated functional kidney recovery, as reflected by significantly lower serum creatinine levels and renal injury score, higher urinary creatinine and creatinine clearance levels (p < 0.05), lower TUNEL-positive cell number, and decreased KIM-1 and NGAL secretion in comparison to the non-treated AKI group. There was no significant difference in any parameters between the MDSPCs and BM-MSCs groups (p > 0.05). Conclusions: MDSPCs and BM-MSCs can migrate and incorporate into injured renal tissue, resulting in a beneficial impact on functional and morphological kidney recovery, which is likely mediated by the secretion of paracrine factors and an anti-apoptotic effect. MDSPCs were found to be non-inferior to BM-MSCs and therefore can be considered as a potential candidate strategy for the treatment of AKI.
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Affiliation(s)
- Egle Pavyde
- Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.P.); (A.U.)
| | - Arvydas Usas
- Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.P.); (A.U.)
| | - Alius Pockevicius
- Pathology Center, Department of Veterinary Pathobiology, Veterinary Academy, Lithuanian University of Health Sciences, LT-47181 Kaunas, Lithuania;
| | - Romaldas Maciulaitis
- Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.P.); (A.U.)
- Department of Nephrology, Medical Academy, Lithuanian University of Health Sciences, LT-50009 Kaunas, Lithuania
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18
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Rzepiński T. In Defense of Expert Knowledge in Bioethical Discussions on Human Genome Editing. THE AMERICAN JOURNAL OF BIOETHICS : AJOB 2023; 23:93-95. [PMID: 38010684 DOI: 10.1080/15265161.2023.2272919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
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19
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Gomes KLG, da Silva RE, da Silva JB, Bosio CGP, Novaes MRCG. Post-marketing authorisation safety and efficacy surveillance of advanced therapy medicinal products in Brazil, the European Union, the United States and Japan. Cytotherapy 2023; 25:1113-1123. [PMID: 37436339 DOI: 10.1016/j.jcyt.2023.06.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/05/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023]
Abstract
BACKGROUND AIMS Advanced therapy medicinal products (ATMPs) are a class of biological products for human use that are based on gene, tissues or cells. ATMPs have peculiar characteristics when compared with traditional medicines. In this regard, long-term safety and efficacy follow-up systems of individuals treated with ATMPs have become necessary and may present unique challenges, because unlike conventional drugs and biologics, these products can exert their effects for years after administration. This work seeks to assess the requirements foreseen in the regulatory frameworks for the post-marketing authorization safety and efficacy surveillance for ATMPs in Brazil, European Union (EU), Japan and United States, which are some of the members of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. METHODS We reviewed the scientific literature and official documents of regulatory agencies (RAs) in Brazil, the EU, Japan and the United States. RESULTS AND CONCLUSIONS RAs in the EU, US and Japan have developed regulatory guidelines for the post-marketing surveillance of ATMPs. These guidelines aim at implementing surveillance plans for monitoring adverse events, including late ones, after marketing authorization. All the ATMPs authorized by the RAs studied, submitted some type of post-marketing requirement to supplement safety and efficacy data, according to the regulations and terminology used by those jurisdictions.
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Affiliation(s)
- Kelly Lucy Guimarães Gomes
- Brazilian Health Regulatory Agency (Anvisa), Brasília, Brazil; Faculty of Health Sciences, University of Brasília (UnB), Brasília, Brazil.
| | | | - João Batista da Silva
- Brazilian Health Regulatory Agency (Anvisa), Brasília, Brazil; Faculty of Health Sciences, University of Brasília (UnB), Brasília, Brazil
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20
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Bellino S, La Salvia A, Cometa MF, Botta R. Cell-based medicinal products approved in the European Union: current evidence and perspectives. Front Pharmacol 2023; 14:1200808. [PMID: 37583902 PMCID: PMC10424920 DOI: 10.3389/fphar.2023.1200808] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/18/2023] [Indexed: 08/17/2023] Open
Abstract
Advanced Therapy Medicinal Products (ATMPs) are innovative clinical treatments exploiting the pharmacological, immunological, or metabolic properties of cells and/or gene(s) with the aim to restore, correct, or modify a biological function in the recipient. ATMPs are heterogeneous medicinal products, developed mainly as individualized and patient-specific treatments, and represent new opportunities for diseases characterized by a high-unmet medical need, including rare, genetic and neurodegenerative disorders, haematological malignancies, cancer, autoimmune, inflammatory and orthopaedic conditions. Into the European Union (EU) market, the first ATMP has been launched in 2009 and, to date, a total of 24 ATMPs have been approved. This review aims at reporting on current evidence of cell-based therapies authorized in the EU, including Somatic Cell Therapies, Tissue Engineering Products, and Cell-based Gene Therapy Products as Chimeric Antigen Receptor (CAR) T-cells, focusing on the evaluation of efficacy and safety in clinical trials and real-world settings. Despite cell-based therapy representing a substantial promise for patients with very limited treatment options, some limitations for its widespread use in the clinical setting remain, including restricted indications, highly complex manufacturing processes, elevated production costs, the lability of cellular products over time, and the potential safety concerns related to the intrinsic characteristics of living cells, including the risk of severe or life-threatening toxicities, such as CAR-T induced neurotoxicity and cytokine release syndrome (CRS). Although encouraging findings support the clinical use of ATMPs, additional data, comparative studies with a long-term follow-up, and wider real-world evidences are needed to provide further insights into their efficacy and safety profiles.
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Affiliation(s)
- Stefania Bellino
- National Center for Drug Research and Evaluation, National Institute of Health (Istituto Superiore di Sanità), Rome, Italy
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21
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Lu J, Xu L, Wei W, He W. Advanced therapy medicinal products in China: Regulation and development. MedComm (Beijing) 2023; 4:e251. [PMID: 37125239 PMCID: PMC10133728 DOI: 10.1002/mco2.251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 05/02/2023] Open
Abstract
Advanced therapy medicinal products (ATMPs) have shown dramatic efficacy in addressing serious diseases over the past decade. With the acceleration and deepening of China's drug regulatory reforms, the country sees a continuous introduction of policies that encourage drug innovation. The capacity and efficiency of the Center for Drug Evaluation (CDE), National Medical Products Administration have significantly improved, where substantial resources have been allocated to ATMPs with major innovations and outstanding clinical values that satisfy urgent clinical needs. These changes have greatly stimulated the research and development of biological products in China, ushering in a period of explosive growth in the number of investigational new drug (IND) applications of ATMPs. Here, we described China's ATMP regulatory framework and analyzed data on IND applications for ATMPs submitted to CDE. The data show that China's ATMP industry is expanding dramatically, but lagging behind in terms of the innovative targets and the coverage of indications. However, in recent years, the diversity of product types, targets, and indications is growing. We discussed challenges and opportunities in ATMP regulation. Risk-based regulation and cross-discipline collaborations are encouraged to promote more ATMPs toward market authorization in China.
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Affiliation(s)
- Jiaqi Lu
- Center for Drug EvaluationNational Medical Products AdministrationBeijingChina
| | - Longchang Xu
- Center for Drug EvaluationNational Medical Products AdministrationBeijingChina
| | - Wei Wei
- Center for Drug EvaluationNational Medical Products AdministrationBeijingChina
| | - Wu He
- Center for Drug EvaluationNational Medical Products AdministrationBeijingChina
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22
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Sagaradze G, Monakova A, Efimenko A. Potency Assays for Mesenchymal Stromal Cell Secretome-Based Products for Tissue Regeneration. Int J Mol Sci 2023; 24:ijms24119379. [PMID: 37298329 DOI: 10.3390/ijms24119379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/21/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Adult stem cells maintaining tissue homeostasis and regeneration are tightly regulated by their specific microenvironments or stem cell niches. The dysfunction of niche components may alter the activity of stem cells and ultimately lead to intractable chronic or acute disorders. To overcome this dysfunction, niche-targeting regenerative medicine treatments such as gene, cell, and tissue therapy are actively investigated. Here, multipotent mesenchymal stromal cells (MSCs), and particularly their secretomes, are of high interest due to their potency to recover and reactivate damaged or lost stem cell niches. However, a workflow for the development of MSC secretome-based products is not fully covered by regulatory authorities, and and this issue significantly complicates their clinical translation and has possibly been expressed in a huge number of failed clinical trials. One of the most critical issues in this regard relates to the development of potency assays. In this review, guidelines for biologicals and cell therapies are considered to be applied for the development of potency assays for the MSC secretome-based products that aim for tissue regeneration. Specific attention is paid to their possible effects on stem cell niches and to a spermatogonial stem cell niche in particular.
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Affiliation(s)
- Georgy Sagaradze
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27/10, Lomonosovskiy av., 119192 Moscow, Russia
| | - Anna Monakova
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27/10, Lomonosovskiy av., 119192 Moscow, Russia
- Faculty of Medicine, Lomonosov Moscow State University, 27/1, Lomonosovskiy av., 119192 Moscow, Russia
| | - Anastasia Efimenko
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27/10, Lomonosovskiy av., 119192 Moscow, Russia
- Faculty of Medicine, Lomonosov Moscow State University, 27/1, Lomonosovskiy av., 119192 Moscow, Russia
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23
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Kuchemüller KB, Pörtner R, Möller J. Design of cell expansion processes for adherent-growing cells with mDoE-workflow. Eng Life Sci 2023; 23:e2200059. [PMID: 37153028 PMCID: PMC10158623 DOI: 10.1002/elsc.202200059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 02/09/2023] [Accepted: 04/01/2023] [Indexed: 05/09/2023] Open
Abstract
Adherent cells, mammalian or human, are ubiquitous for production of viral vaccines, in gene therapy and in immuno-oncology. The development of a cell-expansion process with adherent cells is challenging as scale-up requires the expansion of the cell culture surface. Microcarrier (MC)-based cultures are still predominate. However, the development of MC processes from scratch possesses particular challenges due to their complexity. A novel approach for the reduction of development times and costs of cell propagation processes is the combination of mathematical process models with statistical optimization methods, called model-assisted Design of Experiments (mDoE). In this study, an mDoE workflow was evaluated successfully for the design of a MC-based expansion process of adherent L929 cells at a very early stage of development with limited prior knowledge. At the start, the analytical methods and the screening of appropriate MCs were evaluated. Then, cause-effect relationships (e.g., cell growth related to medium conditions) were worked out, and a mathematical process model was set-up and adapted to experimental data for modeling purposes. The model was subsequently used in mDoE to identify optimized process conditions, which were proven experimentally. An eight-fold increase in cell yield was achieved basically by reducing the initial MC concentration.
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Affiliation(s)
- Kim B. Kuchemüller
- Bioprocess and Biosystems EngineeringHamburg University of TechnologyHamburgGermany
| | - Ralf Pörtner
- Bioprocess and Biosystems EngineeringHamburg University of TechnologyHamburgGermany
| | - Johannes Möller
- Bioprocess and Biosystems EngineeringHamburg University of TechnologyHamburgGermany
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24
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de Kanter AFJ, Jongsma KR, Verhaar MC, Bredenoord AL. The Ethical Implications of Tissue Engineering for Regenerative Purposes: A Systematic Review. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:167-187. [PMID: 36112697 PMCID: PMC10122262 DOI: 10.1089/ten.teb.2022.0033] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/30/2022] [Indexed: 11/12/2022]
Abstract
Tissue Engineering (TE) is a branch of Regenerative Medicine (RM) that combines stem cells and biomaterial scaffolds to create living tissue constructs to restore patients' organs after injury or disease. Over the last decade, emerging technologies such as 3D bioprinting, biofabrication, supramolecular materials, induced pluripotent stem cells, and organoids have entered the field. While this rapidly evolving field is expected to have great therapeutic potential, its development from bench to bedside presents several ethical and societal challenges. To make sure TE will reach its ultimate goal of improving patient welfare, these challenges should be mapped out and evaluated. Therefore, we performed a systematic review of the ethical implications of the development and application of TE for regenerative purposes, as mentioned in the academic literature. A search query in PubMed, Embase, Scopus, and PhilPapers yielded 2451 unique articles. After systematic screening, 237 relevant ethical and biomedical articles published between 2008 and 2021 were included in our review. We identified a broad range of ethical implications that could be categorized under 10 themes. Seven themes trace the development from bench to bedside: (1) animal experimentation, (2) handling human tissue, (3) informed consent, (4) therapeutic potential, (5) risk and safety, (6) clinical translation, and (7) societal impact. Three themes represent ethical safeguards relevant to all developmental phases: (8) scientific integrity, (9) regulation, and (10) patient and public involvement. This review reveals that since 2008 a significant body of literature has emerged on how to design clinical trials for TE in a responsible manner. However, several topics remain in need of more attention. These include the acceptability of alternative translational pathways outside clinical trials, soft impacts on society and questions of ownership over engineered tissues. Overall, this overview of the ethical and societal implications of the field will help promote responsible development of new interventions in TE and RM. It can also serve as a valuable resource and educational tool for scientists, engineers, and clinicians in the field by providing an overview of the ethical considerations relevant to their work. Impact statement To our knowledge, this is the first time that the ethical implications of Tissue Engineering (TE) have been reviewed systematically. By gathering existing scholarly work and identifying knowledge gaps, this review facilitates further research into the ethical and societal implications of TE and Regenerative Medicine (RM) and other emerging biomedical technologies. Moreover, it will serve as a valuable resource and educational tool for scientists, engineers, and clinicians in the field by providing an overview of the ethical considerations relevant to their work. As such, our review may promote successful and responsible development of new strategies in TE and RM.
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Affiliation(s)
- Anne-Floor J. de Kanter
- Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Karin R. Jongsma
- Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Marianne C. Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Annelien L. Bredenoord
- Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Erasmus School of Philosophy, Erasmus University Rotterdam, Rotterdam, The Netherlands
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25
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Kropp M, Harmening N, Bascuas T, Johnen S, De Clerck E, Fernández V, Ronchetti M, Cadossi R, Zanini C, Scherman D, Ivics Z, Marie C, Izsvák Z, Thumann G. GMP-Grade Manufacturing and Quality Control of a Non-Virally Engineered Advanced Therapy Medicinal Product for Personalized Treatment of Age-Related Macular Degeneration. Biomedicines 2022; 10:2777. [PMID: 36359296 PMCID: PMC9687277 DOI: 10.3390/biomedicines10112777] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 09/29/2023] Open
Abstract
The introduction of new therapeutics requires validation of Good Manufacturing Practice (GMP)-grade manufacturing including suitable quality controls. This is challenging for Advanced Therapy Medicinal Products (ATMP) with personalized batches. We have developed a person-alized, cell-based gene therapy to treat age-related macular degeneration and established a vali-dation strategy of the GMP-grade manufacture for the ATMP; manufacturing and quality control were challenging due to a low cell number, batch-to-batch variability and short production duration. Instead of patient iris pigment epithelial cells, human donor tissue was used to produce the transfected cell product ("tIPE"). We implemented an extended validation of 104 tIPE productions. Procedure, operators and devices have been validated and qualified by determining cell number, viability, extracellular DNA, sterility, duration, temperature and volume. Transfected autologous cells were transplanted to rabbits verifying feasibility of the treatment. A container has been engineered to ensure a safe transport from the production to the surgery site. Criteria for successful validation and qualification were based on tIPE's Critical Quality Attributes and Process Parameters, its manufacture and release criteria. The validated process and qualified operators are essential to bring the ATMP into clinic and offer a general strategy for the transfer to other manufacture centers and personalized ATMPs.
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Affiliation(s)
- Martina Kropp
- Group of Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Department of Ophthalmology, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Nina Harmening
- Group of Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Department of Ophthalmology, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Thais Bascuas
- Group of Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Department of Ophthalmology, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Sandra Johnen
- Department of Ophthalmology, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Eline De Clerck
- Group of Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Department of Ophthalmology, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | | | | | | | | | - Daniel Scherman
- CNRS, Inserm, UTCBS, Université Paris Cité, F-75006 Paris, France
| | - Zoltán Ivics
- Division of Medical Biotechnology, Paul-Ehrlich-Institute, 63225 Langen, Germany
| | - Corinne Marie
- CNRS, Inserm, UTCBS, Université Paris Cité, F-75006 Paris, France
- Chimie ParisTech, PSL Research University, F-75005 Paris, France
| | - Zsuzsanna Izsvák
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
| | - Gabriele Thumann
- Group of Experimental Ophthalmology, University of Geneva, 1205 Geneva, Switzerland
- Department of Ophthalmology, University Hospitals of Geneva, 1205 Geneva, Switzerland
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26
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de Jongh D, Massey EK, Cronin AJ, Schermer MHN, Bunnik EM, the VANGUARD Consortium. Early-Phase Clinical Trials of Bio-Artificial Organ Technology: A Systematic Review of Ethical Issues. Transpl Int 2022; 35:10751. [PMID: 36388425 PMCID: PMC9659568 DOI: 10.3389/ti.2022.10751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 10/07/2022] [Indexed: 01/25/2023]
Abstract
Regenerative medicine has emerged as a novel alternative solution to organ failure which circumvents the issue of organ shortage. In preclinical research settings bio-artificial organs are being developed. It is anticipated that eventually it will be possible to launch first-in-human transplantation trials to test safety and efficacy in human recipients. In early-phase transplantation trials, however, research participants could be exposed to serious risks, such as toxicity, infections and tumorigenesis. So far, there is no ethical guidance for the safe and responsible design and conduct of early-phase clinical trials of bio-artificial organs. Therefore, research ethics review committees will need to look to related adjacent fields of research, including for example cell-based therapy, for guidance. In this systematic review, we examined the literature on early-phase clinical trials in these adjacent fields and undertook a thematic analysis of relevant ethical points to consider for early-phase clinical trials of transplantable bio-artificial organs. Six themes were identified: cell source, risk-benefit assessment, patient selection, trial design, informed consent, and oversight and accountability. Further empirical research is needed to provide insight in patient perspectives, as this may serve as valuable input in determining the conditions for ethically responsible and acceptable early clinical development of bio-artificial organs.
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Affiliation(s)
- Dide de Jongh
- Department of Nephrology and Transplantation, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands,Department of Medical Ethics, Philosophy and History of Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands,*Correspondence: Dide de Jongh,
| | - Emma K. Massey
- Department of Nephrology and Transplantation, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Antonia J. Cronin
- Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom,King’s College, London, United Kingdom
| | - Maartje H. N. Schermer
- Department of Medical Ethics, Philosophy and History of Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands
| | - Eline M. Bunnik
- Department of Medical Ethics, Philosophy and History of Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, Netherlands
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27
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Rusconi G, Cusumano G, Mariotta L, Canevascini R, Gola M, Gornati R, Soldati G. Upgrading Monocytes Therapy for Critical Limb Ischemia Patient Treatment: Pre-Clinical and GMP-Validation Aspects. Int J Mol Sci 2022; 23:ijms232012669. [PMID: 36293525 PMCID: PMC9604444 DOI: 10.3390/ijms232012669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/12/2022] [Accepted: 10/17/2022] [Indexed: 12/03/2022] Open
Abstract
Advanced cell therapy medicinal products (ATMP) are at the forefront of a new range of biopharmaceuticals. The use of ATMP has evolved and increased in the last decades, representing a new approach to treating diseases that are not effectively managed with conventional treatments. The standard worldwide recognized for drug production is the Good Manufacturing Practices (GMP), widely used in the pharma production of synthesized drugs but applying also to ATMP. GMP guidelines are worldwide recognized standards to manufacture medicinal products to guarantee high quality, safety, and efficacy. In this report, we describe the pre-clinical and the GMP upgrade of peripheral blood mononuclear cell (PBMC) preparation, starting from peripheral blood and ending up with a GMP-grade clinical product ready to be used in patients with critical limb ischemia (CLI). We also evaluated production in hypoxic conditions to increase PBMC functional activity and angiogenic potential. Furthermore, we extensively analyzed the storage and transport conditions of the final product as required by the regulatory body for ATMPs. Altogether, results suggest that the whole manufacturing process can be performed for clinical application. Peripheral blood collected by a physician should be transported at room temperature, and PBMCs should be isolated in a clean room within 8 h of venipuncture. Frozen cells can be stored in nitrogen vapors and thawed for up to 12 months. PBMCs resuspended in 5% human albumin solution should be stored and transported at 4 °C before injection in patients within 24 h to thawing. Hypoxic conditioning of PBMCs should be implemented for clinical application, as it showed a significant enhancement of PBMC functional activity, in particular with increased adhesion, migration, and oxidative stress resistance. We demonstrated the feasibility and the quality of a GMP-enriched suspension of monocytes as an ATMP, tested in a clean room facility for all aspects related to production in respect of all the GMP criteria that allow its use as an ATMP. We think that these results could ease the way to the clinical application of ATMPs.
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Affiliation(s)
| | | | - Luca Mariotta
- Swiss Stem Cell Foundation, 6900 Lugano, Switzerland
| | - Reto Canevascini
- Department of Surgery, Service of Angiology, Lugano Regional Hospital, 6900 Lugano, Switzerland
| | - Mauro Gola
- Swiss Stem Cell Foundation, 6900 Lugano, Switzerland
| | - Rosalba Gornati
- Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Gianni Soldati
- Swiss Stem Cell Foundation, 6900 Lugano, Switzerland
- Correspondence:
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28
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Gindraux F, Hofmann N, Agudo-Barriuso M, Antica M, Couto PS, Dubus M, Forostyak S, Girandon L, Gramignoli R, Jurga M, Liarte S, Navakauskiene R, Shablii V, Lafarge X, Nicolás FJ. Perinatal derivatives application: Identifying possibilities for clinical use. Front Bioeng Biotechnol 2022; 10:977590. [PMID: 36304904 PMCID: PMC9595339 DOI: 10.3389/fbioe.2022.977590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/04/2022] [Indexed: 11/13/2022] Open
Abstract
Perinatal derivatives are drawing growing interest among the scientific community as an unrestricted source of multipotent stromal cells, stem cells, cellular soluble mediators, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options by means of developing regenerative approaches. In this paper, to generate a complete view of the state of the art, a comprehensive 10-years compilation of clinical-trial data with the common denominator of PnD usage has been discussed, including commercialized products. A set of criteria was delineated to challenge the 10-years compilation of clinical trials data. We focused our attention on several aspects including, but not limited to, treated disorders, minimal or substantial manipulation, route of administration, dosage, and frequency of application. Interestingly, a clear correlation of PnD products was observed within conditions, way of administration or dosage, suggesting there is a consolidated clinical practice approach for the use of PnD in medicine. No regulatory aspects could be read from the database since this information is not mandatory for registration. The database will be publicly available for consultation. In summary, the main aims of this position paper are to show possibilities for clinical application of PnD and propose an approach for clinical trial preparation and registration in a uniform and standardized way. For this purpose, a questionnaire was created compiling different sections that are relevant when starting a new clinical trial using PnD. More importantly, we want to bring the attention of the medical community to the perinatal products as a consolidated and efficient alternative for their use as a new standard of care in the clinical practice.
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29
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Muthu S, Jeyaraman M, Kotner MB, Jeyaraman N, Rajendran RL, Sharma S, Khanna M, Rajendran SNS, Oh JM, Gangadaran P, Ahn BC. Evolution of Mesenchymal Stem Cell Therapy as an Advanced Therapeutic Medicinal Product (ATMP)-An Indian Perspective. Bioengineering (Basel) 2022; 9:111. [PMID: 35324800 PMCID: PMC8945480 DOI: 10.3390/bioengineering9030111] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 02/05/2023] Open
Abstract
Stem cells can be defined as the cells that have the capacity to both self-renew and give rise to differentiated cells. Under the right conditions and signals, depending on their origin and bio-plasticity, stem cells can differentiate into multiple cell lineages and develop into various mature cells. Stem cell therapy is a fast-developing branch of medicine that includes the most innovative regenerative therapies for the restoration of cell and tissue function in individuals with severe diseases. Stem cell research has resulted in the emergence of cell-based therapies for disorders that are resistant to conventional drugs and therapies, and they are considered under the category of an Advanced Therapeutic Medicinal Product (ATMP). The FDA and the European Medicines Agency (EMA) devised a new strategy in 2017 with the aim of unifying the standards for development of ATMPs such that it is easy to exchange information at the international level. In this review, we discuss the evolution of mesenchymal stem cell-based therapy as an ATMP in the global and Indian scenarios, along with the guidelines governing their usage and clinical application of these therapeutics.
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Affiliation(s)
- Sathish Muthu
- Department of Orthopaedics, Government Medical College and Hospital, Dindigul 624001, India;
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, India
| | - Madhan Jeyaraman
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida 201310, India
- Department of Orthopaedics, Faculty of Medicine-Sri Lalithambigai Medical College and Hospital, Dr. MGR Educational and Research Institute University, Chennai 600095, India
| | - Moinuddin Basha Kotner
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. Ram Manohar Lohiya National Law University, Lucknow 226012, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
- Fellow in Orthopaedic Rheumatology, Dr. Ram Manohar Lohiya National Law University, Lucknow 226012, India
- Fellow in Joint Replacement, Atlas Hospitals, The Tamil Nadu Dr. MGR Medical University, Tiruchirappalli 620002, India
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea; (R.L.R.); (J.M.O.)
| | - Shilpa Sharma
- Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Manish Khanna
- Indian Stem Cell Study Group, Lucknow 226010, India; (M.B.K.); (N.J.); (M.K.)
| | - Sree Naga Sowndary Rajendran
- Department of Medicine, Sri Venkateshwaraa Medical College Hospital and Research Centre, Puducherry 605107, India;
| | - Ji Min Oh
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea; (R.L.R.); (J.M.O.)
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea; (R.L.R.); (J.M.O.)
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea; (R.L.R.); (J.M.O.)
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41944, Korea
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30
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Pizevska M, Kaeda J, Fritsche E, Elazaly H, Reinke P, Amini L. Advanced Therapy Medicinal Products' Translation in Europe: A Developers' Perspective. Front Med (Lausanne) 2022; 9:757647. [PMID: 35186986 PMCID: PMC8851388 DOI: 10.3389/fmed.2022.757647] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
Advanced Therapy Medicinal Products (ATMPs) comprising cell, gene, and tissue-engineered therapies have demonstrated enormous therapeutic benefits. However, their development is complex to be managed efficiently within currently existing regulatory frameworks. Legislation and regulation requirements for ATMPs must strike a balance between the patient safety while promoting innovations to optimize exploitation of these novel therapeutics. This paradox highlights the importance of on-going dynamic dialogue between all stakeholders and regulatory science to facilitate the development of pragmatic ATMP regulatory guidelines.
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Affiliation(s)
- Maja Pizevska
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
| | - Jaspal Kaeda
- Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Enrico Fritsche
- Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Hisham Elazaly
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.,Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Leila Amini
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.,Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, Berlin, Germany
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31
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Umemura M, Morrison M. Comparative lessons in regenerative medicine readiness: learning from the UK and Japanese experience. Regen Med 2021; 16:269-282. [PMID: 33781099 DOI: 10.2217/rme-2020-0136] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
This paper explores how 'regenerative readiness' varies between different national research and healthcare systems. Here, 'readiness' refers to both the readiness of a given technology and the ability of a given setting to adopt a new technology. We compare two settings that have taken active yet dissonant approaches to improve readiness: the UK and Japan. Existing scholarship observes that disruptive technologies such as regenerative medicine require many adaptations to become useable and function along the principles of their design. We incorporate the sociotechnical systems framework to consider the range of adaptive measures taken across elements of the sociotechnical system for novel technological adoption. Building upon existing works on technology readiness and institutional readiness, we also expand the conceptualization of readiness toward system-wide readiness.
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Affiliation(s)
- Maki Umemura
- Senior Lecturer in International Business, Cardiff Business School, Cardiff University, Aberconway Building, Colum Drive, Cardiff, CF10 3EU, UK
| | - Michael Morrison
- Senior Researcher in Social Science, Centre for Health, Law & Emerging Technologies, Faculty of Law, University of Oxford, Ewert House, Banbury Road, Oxford, OX2 7DD, UK.,Research Affiliate, Institution for Science Innovation & Society, School of Anthropology & Museum Ethnography, University of Oxford, 51/53 Banbury Road, Oxford, OX2 6PE, UK
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