ASGCT 22nd Annual Meeting Abstracts

Johansson, Magnus; Frelin, Lars; Maravelia, Panagiota; Asghar, Naveed; Melik, Wessam; Caro-Pérez, Noelia; Pasetto, Anna; Ahlén, Gustaf; Sällberg, Matti

doi:10.1016/j.ymthe.2019.04.004

Cited by 6 publications

(2 citation statements)

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“…Prostaglandin E2 (PGE 2 ) allows enhanced transduction efficiency in one hit protocol thus limiting HSPC manipulation (83,84). Consistently, PGE 2 has been recently applied in a GT phase I/II clinical trial to treat mucopolysaccharidosis type I, Hurler Syndrome (85).…”

Section: Discussionmentioning

confidence: 99%

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency

2020

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Genetic defects in recombination activating genes (RAG) 1 and 2 cause a broad spectrum of severe immune defects ranging from early severe and repeated infections to inflammation and autoimmune manifestations. A correlation between in vitro recombination activity and immune phenotype has been described. Hematopoietic cell transplantation is the treatment of care; however, the availability of next generation sequencing and whole genome sequencing has allowed the identification of novel genetic RAG variants in immunodeficient patients at various ages, raising therapeutic questions. This review addresses the recent advances of novel therapeutic approaches for RAG deficiency. As conventional myeloablative conditioning regimens are associated with acute toxicities and transplanted-related mortality, innovative minimal conditioning regimens based on the use of monoclonal antibodies are now emerging and show promising results. To overcome shortage of compatible donors, gene therapy has been developed in various RAG preclinical models. Overall, the transplantation of autologous gene corrected hematopoietic precursors and the use of non-genotoxic conditioning will open a new era, offering a cure to an increasing number of RAG patients regardless of donor availability and severity of clinical conditions.

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Section: Discussionmentioning

confidence: 99%

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency

2020

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“…In particular, it is mandatory for modern biological products that have recently been introduced to the market, for which data about unique or combined sequential therapies (AAV, ASO and RNAi for example) require to be expanded. This is of importance in the context of potential immune adverse reactions following repeat deliveries that may be necessary for some patients (Poster 147 in [255]). Of note, the number of research dogs could be further reduced by including affected pets in preclinical trials, with the consent of their owners.…”

Section: Discussionmentioning

confidence: 99%

The Dog Model in the Spotlight: Legacy of a Trustful Cooperation

Barthélémy

Hitte

Tiret

2019

JND

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Dogs have long been used as a biomedical model system and in particular as a preclinical proof of concept for innovative therapies before translation to humans. A recent example of the utility of this animal model is the promising myotubularin gene delivery in boys affected by X-linked centronuclear myopathy after successful systemic, long-term efficient gene therapy in Labrador retrievers. Mostly, this is due to unique features that make dogs an optimal system. The continuous emergence of spontaneous inherited disorders enables the identification of reliable complementary molecular models for human neuromuscular disorders (NMDs). Dogs’ characteristics including size, lifespan and unprecedented medical care level allow a comprehensive longitudinal description of diseases. Moreover, the highly similar pathogenic mechanisms with human patients yield to translational robustness. Finally, interindividual phenotypic heterogeneity between dogs helps identifying modifiers and anticipates precision medicine issues.This review article summarizes the present list of molecularly characterized dog models for NMDs and provides an exhaustive list of the clinical and paraclinical assays that have been developed. This toolbox offers scientists a sensitive and reliable system to thoroughly evaluate neuromuscular function, as well as efficiency and safety of innovative therapies targeting these NMDs. This review also contextualizes the model by highlighting its unique genetic value, shaped by the long-term coevolution of humans and domesticated dogs. Because the dog is one of the most protected research animal models, there is considerable opposition to include it in preclinical projects, posing a threat to the use of this model. We thus discuss ethical issues, emphasizing that unlike many other models, the dog also benefits from its contribution to comparative biomedical research with a drastic reduction in the prevalence of morbid alleles in the breeding stock and an improvement in medical care.

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Assessment of quality attributes for adeno‐associated viral vectors

Tustian

Bak

2021

Biotech & Bioengineering

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There is a strong and growing interest in the development and production of gene therapy products, including those utilizing adeno-associated virus (AAV) particles. This is evident with the increase in the number of clinical trials and agency approvals for AAV therapeutics. As bioproduction of AAV viral vectors matures, a quality by design (QbD) approach to process development can aid in process robustness and product quality. Furthermore, it may become a regulatory expectation. The first step in any QbD approach is to determine what physical, chemical, biological, or microbiological property or characteristic product attributes should be controlled within an appropriate limit, range, or distribution to ensure the desired product quality.Then predefined goals are set to allow proactive process development to design in quality. This review lists typical quality attributes used for release testing of AAV viral vectors and discusses these and selected attributes important to extended characterization studies in terms of safety, efficacy, and impact upon the patient immune response. K E Y W O R D S adeno-associated virus, analytics, critical quality attribute, gene therapy, quality by design 1 | INTRODUCTION Adeno-associated virus (AAV)-based viral vectors have shown enormous potential in recent years for use in gene therapy as a therapeutic modality to treat a wide range of genetic diseases, with more than 150 clinical trials specific to AAV (Penaud-Budloo et al., 2018).AAV treatments first gained regulatory approval in the European Union, with alipogene tiparvovec's (Glybera, uniQure) approval in 2012 for lipoprotein lipase deficiency. The first US regulatory ap-

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ASGCT 22nd Annual Meeting Abstracts

Cited by 6 publications

References 0 publications

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency

The Dog Model in the Spotlight: Legacy of a Trustful Cooperation

Assessment of quality attributes for adeno‐associated viral vectors

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