AAV Vector for Muscle Gene Therapy

Authors

Creative Biogene

Summary

Adeno-associated virus (AAV) vectors have been identified as promising gene delivery candidates due to their ability to transduce muscle tissue efficiently while transporting a genetic payload. Currently, there is significant momentum in the research of AAV-mediated delivery of muscle genes. Various AAV-based therapeutic strategies are undergoing preclinical and clinical testing, including the use of miniaturized and codon-optimized transgenes, exon skipping expression cassettes, novel tissue-specific promoters, AAV capsid mutants and chimeras, and localized intravascular administration procedures.

Introduction

rAAV vector of various serotypes has recently gained attention as potentially useful gene transfer vehicles, many of which can deliver therapeutic transgenes to cardiac and skeletal muscles. Multiple routes of vector administration proved to achieve either localized or widespread muscle gene transfer, both of which have potential applications and drawbacks in clinical use. Route of administration significantly influences the biodistribution and transduction efficiency of rAAV vectors in vivo.

Direct intramuscular injection is a simple method that allows for local vector delivery to a targeted area of skeletal muscle. rAAV1 and rAAV2 are commonly used in directly targeting skeletal muscle for local gene transfer. Intramuscularly delivered rAAV vectors of other serotypes, such as rAAV6, 7, 8 and 9, can also lead to robust transgene expression in the injected muscle as well as some other tissues to which those vectors are spread via blood circulation. Since gene therapy for most muscle diseases requires whole-body muscle gene transfer, localized intramuscular vector delivery is not practical in these cases. However, if muscle-targeted gene transfer is used to produce secretory proteins, such as blood clotting factor VIII and IX, human a1 antitrypsin (A1AT) and erythropoietin (EPO), intramuscular administration of vectors is indeed valuable. The second route for regional muscle delivery is retrograde transvenous limb perfusion, which targets a larger number of muscle groups. It delivers rAAV vectors to the entire muscle mass of the limb, which could be useful for the treatment of diseases that affect large muscle mass. This method of rAAV delivery has been used in clinical trials for muscle gene transfer to treat muscle diseases such as Duchenne muscular dystrophy (DMD).

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