Considerations on Preclinical Neuromuscular Disease Gene Therapy Studies

Duan, Dongsheng

doi:10.1007/978-3-030-03095-7_17

Cited by 6 publications

(6 citation statements)

References 254 publications

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“…Collectively, these studies suggest that muscle function improvement can occur independent of muscle pathology amelioration. 47 In summary, our study has provided compelling evidence to pursue disease gene-independent SERCA2a gene therapy to treat DMD.…”

Section: Discussionmentioning

confidence: 80%

Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy

et al. 2020

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Loss of dystrophin leads to Duchenne muscular dystrophy (DMD). A pathogenic feature of DMD is the significant elevation of cytosolic calcium. Supraphysiological calcium triggers protein degradation, membrane damage, and eventually muscle death and dysfunction. Sarcoplasmic/endoplasmic reticulum (SR) calcium ATPase (SERCA) is a calcium pump that transports cytosolic calcium to the SR during excitationcontraction coupling. We hypothesize that a single systemic delivery of SERCA2a with adeno-associated virus (AAV) may improve calcium recycling and provide long-lasting benefits in DMD. To test this, we injected an AAV9 human SERCA2a vector (6 Â 10 12 viral genome particles/mouse) intravenously to 3-month-old mdx mice, the most commonly used DMD model. Immunostaining and western blot showed robust human SERCA2a expression in the heart and skeletal muscle for 18 months. Concomitantly, SR calcium uptake was significantly improved in these tissues. SERCA2a therapy significantly enhanced grip force and treadmill performance, completely prevented myocardial fibrosis, and normalized electrocardiograms (ECGs). Cardiac catheterization showed normalization of multiple systolic and diastolic hemodynamic parameters in treated mice. Importantly, chamber dilation was completely prevented, and ejection fraction was restored to the wild-type level. Our results suggest that a single systemic AAV9 SERCA2a therapy has the potential to provide long-lasting benefits for DMD.

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Section: Discussionmentioning

confidence: 80%

Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy

et al. 2020

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“…This is in addition to the use of muscle delivery for indirect therapeutic purposes. It is worth noting that the treatment of hereditary muscular diseases is complicated by the total volume of muscle tissue, which is half of the total body mass, poor accessibility of deep muscles, and progressive tissue remodeling that is characteristic of the natural course of diseases [172].…”

Section: Muscle Targetingmentioning

confidence: 99%

Non-Viral Carriers for Nucleic Acids Delivery: Fundamentals and Current Applications

Shtykalova

Deviatkin

Freund

et al. 2023

Life

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Over the past decades, non-viral DNA and RNA delivery systems have been intensively studied as an alternative to viral vectors. Despite the most significant advantage over viruses, such as the lack of immunogenicity and cytotoxicity, the widespread use of non-viral carriers in clinical practice is still limited due to the insufficient efficacy associated with the difficulties of overcoming extracellular and intracellular barriers. Overcoming barriers by non-viral carriers is facilitated by their chemical structure, surface charge, as well as developed modifications. Currently, there are many different forms of non-viral carriers for various applications. This review aimed to summarize recent developments based on the essential requirements for non-viral carriers for gene therapy.

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“…General categories include gene replacement, gene modulation, gene correction, and gene knockdown ( figures 12-2g , 12-2h , and 12-3f to 12-3h ). 16 Recessive loss-of-function and dominant haploinsufficiency disorders are the primary target of gene replacement and repair strategies. Gene replacement provides a functional copy of the mutated gene, whereas gene modulation modifies the mutation for functional benefit (eg, exon skipping, stop codon read-through) ( figures 12-2g and 12-2h ).…”

Section: Genetic Treatment Strategies Employed In Neuromuscular Medicinementioning

confidence: 99%

Genetic-Based Treatment Strategies for Muscular Dystrophy and Congenital Myopathies

Findlay¹,

Weihl²

2022

CONTINUUM: Lifelong Learning in Neurology

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PURPOSE OF REVIEW: This article discusses the foundational concepts of genetic treatment strategies employed in neuromuscular medicine, as well as the importance of genetic testing as a requirement for applying gene-based therapy.RECENT FINDINGS: Gene therapies have become a reality for several neuromuscular disorders. Exon-skipping and (in Europe) ribosomal read-through approaches are currently available to a subset of patients with Duchenne muscular dystrophy. Microdystrophin gene replacement has shown promise and is nearing the final stages of clinical trials. Numerous gene-based therapies for other muscular dystrophies and congenital myopathies are progressing toward approval as well.SUMMARY: Muscular dystrophies and congenital myopathies are a heterogenous group of hereditary muscle disorders. Confirming a diagnosis with genetic testing is not only critical for guiding management, but also an actual prerequisite for current and future gene therapies. Recessive loss-of-function or dominant haploinsufficiency disorders may be treated with gene replacement strategies, whereas dominant negative and toxic gain-of-function disorders are best addressed with a variety of knockdown approaches. It is important to recognize that many therapeutics are mutation specific and will only benefit a subset of individuals with a specific disease.

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Considerations on Preclinical Neuromuscular Disease Gene Therapy Studies

Cited by 6 publications

References 254 publications

Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy

Single SERCA2a Therapy Ameliorated Dilated Cardiomyopathy for 18 Months in a Mouse Model of Duchenne Muscular Dystrophy

Non-Viral Carriers for Nucleic Acids Delivery: Fundamentals and Current Applications

Genetic-Based Treatment Strategies for Muscular Dystrophy and Congenital Myopathies

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