The global industry is well aware of these challenges. Some are dumping viral capsids as delivery shuttles. Some are looking for viruses that are safer in humans. Some are trying to develop safer viral vectors.
Sarepta Therapeutics has taken an over-the-top approach in its quest for solutions, but the most promising one to date is based on developing better AAV vectors.
The genetic medicine leader has teamed up with the Broad Institute, one of the world’s leading research labs and one of the pioneers behind CRISPR gene editing, to develop a series of next-generation delivery shuttles called MyoAAV.
After confirming the collaborator’s work in its own labs, Sarepta Therapeutics has hailed the tools as a potential breakthrough in precision genetic medicine.
A press release highlighted four primary improvements in MyoAAV delivery shuttles compared to natural AAV vectors, as measured in preclinical studies in non-human primates:
An up to 50x improvement in gene expression in muscle tissues.
An up to 15x improvement in gene expression in cardiac tissues.
Reduced delivery to and accumulation in the liver (an “off-target” tissue for diseases in the company’s pipeline).
The potential to be used at up to 10x lower doses. Gene therapy doses are determined on an exponential scale, so this isn’t as impressive as it sounds. Nevertheless, this can yield significant improvements in safety, cost and production.
Sarepta Therapeutics has obtained an exclusive license to use MyoAAV delivery shuttles for five different diseases, including DMD, with options for additional targets. The license appears to include both gene therapy and gene editing loads.
Will the next-generation tools be a real breakthrough? The early preclinical data certainly looks promising. Of course, it is important to acknowledge the careful wording of the press release.
Many of the improvements were expressed as ‘up to’, while a closer look at the scientific literature and competitive landscape shows that comparisons to natural AAV capsids can be misleading. A handful of well-funded startups are developing next-generation AAV capsids, which would provide a better comparison. On the other hand, Sarepta Therapeutics forged partnerships across the landscape and seems to have chosen MyoAAV for clinical trials.
It’s also important for investors to recognize one unrecognized drawback: MyoAAV delivery shuttles will still have relatively low capacity. That will force Sarepta Therapeutics to continue using miniaturized versions of replacement genes instead of full-length human copies. Higher delivery efficiency should reduce the impact of this limitation, but the downside looms.
MyoAAV won’t be a major driver of Sarepta Therapeutics stock for the foreseeable future, but investors can be happy that the company is scaling down its bets as it heads to the clinic. Data reported in the coming years will determine whether the bets pay off.