A new family of adeno-associated virus (AAV) capsid variants that enable the delivery of the desired gene specifically to muscles was introduced by Mohammadsharif Tabebordbar, PhD, cofounder and chief scientific officer at Kate Therapeutics, at the 2022 Muscular Dystrophy Association Clinical & Scientific Conference.
The new variants could be a promising tool for gene therapy to treat myopathies such as Duchenne muscular dystrophy (DMD). They may also have fewer side effects, as they allow the delivery of healthy copies of mutated genes specifically to muscle tissues.
Using a technique called directed evolution of AAV capsid leveraging in vivo expression of transgene RNA (DELIVER), researchers identified a family of muscle-tropic capsids in a mouse model.
They tested the efficacy of the capsid that they called myoAAV by delivering the gene coding for a green fluorescent protein (GFP) to different tissues in the animals. They found that transduction was very efficient compared to adeno-associated virus serotype 9 (AAV9) and was specific to muscle tissue, with almost no GFP expression in other tissues.
Read more about gene therapy for DMD.
The researchers also compared the expression of the transgene delivered by myoAAV in the mice compared to AAV9 and adeno-associated virus serotype 8 (AAV8) and found that expression was much higher when the transgene was delivered using myoAAV.
When they used myoAAV to deliver the human gene coding for myotubularin under a muscle promoter to the body of mice lacking myotubularin, the researchers saw that the survival of the animals was improved. “They were not only alive but they also gained weight,” Dr. Tabebordbar said. Moreover, their activity was not distinguishable from that of wild-type animals.
Finally, the researchers conducted some experiments in which they used myoAAV to deliver a gene coding for microdystrophin to the body of the animals and compared that to AAV9. They saw that transduction efficacy was much higher with myoAAV.
The researchers are now working on second-generation myotropic capsid variants in the mice that could deliver the transgene even more efficiently to the muscles.
Tabebordbar M. Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Oral presentation at: 2022 Muscular Dystrophy Association Clinical & Scientific Conference; March 16, 2022; Nashville, TN