Use of a Lower Dosage Liver-Detargeted AAV Vector to Prevent Hamster Muscular Dystrophy

Abstract

The BIO14.6 hamster carries a mutation in the delta sarcoglycan gene causing muscular dystrophy and cardiomyopathy. The disease can be prevented by systemic delivery of delta sarcoglycan cDNA using adeno-associated viruses (AAVs). However, all AAVs also target the liver, raising concerns about their therapeutic efficacy in human applications. We compared the AAV2/8 with the chimeric AAV2/2i8, in which the 585-QQNTAP-590 motif of the AAV8 serotype was added to the heparan sulfate receptor footprint of the AAV2 strain. Both vectors carrying the human delta sarcoglycan cDNA were delivered into 24 14-day-old BIO14.6 hamsters. We followed transgene expression in muscle and liver for 7 months. We detected a sustained ectopic expression of delta sarcoglycan in the liver when using AAV2/8 but not AAV2/2i8. Genomic copies of AAV2/2i8 were not detectable in the liver, while at least 100-fold more copies of AAV2/8 were counted. In contrast, the hamster skeletal muscle expressed more delta sarcoglycan using AAV2/2i8 and were still healthy after 7 months at the lower dosage. We conclude that this chimeric vector is a robust option for safer and longer-term diseased muscle targeting.

Recent advances in gene therapy for atrial fibrillation

“…Each serotype has a distinct capsid protein sequence correlating to variable tissue tropism, with AAV serotypes 1, 6, 8, and 9 exhibiting the highest cardiac tropism 35,36 . By engineering the makeup of the viral capsid proteins, it is possible to generate novel, chimeric AAVs with improved transduction efficiency and tropism in rodent models 37–39 . Tissue specificity can also be achieved with the use of site specific promoters to drive transgene expression only in the atria 40 .…”

“…35,36 By engineering the makeup of the viral capsid proteins, it is possible to generate novel, chimeric AAVs with improved transduction efficiency and tropism in rodent models. [37][38][39] Tissue specificity can also be achieved with the use of site specific promoters to drive transgene expression only in the atria. 40 While transduction efficiency is often more limited in scale-up from rodent to large animal models, these emerging strategies are accompanied with recent Food and Drug Administration-approval for noncardiac gene therapies and a number of clinical trials utilizing an AAV vector.…”

Recent Advances in Gene Therapy for Atrial Fibrillation

“…35,36 By engineering the makeup of the viral capsid proteins, it is possible to generate novel, chimeric AAVs with improved transduction efficiency and tropism in rodent models. [37][38][39] Tissue specificity can also be achieved with the use of site specific promoters to drive transgene expression only in the atria. 40 While transduction efficiency is often more limited in scale-up from rodent to large animal models, these emerging strategies are accompanied with recent FDA-approval for non-cardiac gene therapies and a number of clinical trials utilizing an AAV vector.…”

Advancements in the design and scalable production of viral gene transfer vectors

“…AAV vectors, like adenovirus, are subject to sequestration in the liver, perhaps not surprisingly since AAV evolved to coinfect the same cells are its helper virus (Rotundo et al, 2013). Though AAV liver sequestration is not associated with the severe inflammatory response observed in early trials with adenovirus vectors, sequestration does prevent efficient tissue targeting (Zaiss & Muruve, 2005).…”