Researchers based at Harvard and the Broad Institute have adapted currently used gene therapy vectors to make them more suitable for targeting muscular conditions such as Duchenne muscular dystrophy and also to make them less toxic to patients.
One of the most common methods for delivering gene therapy today is using engineered adeno-associated viruses (AAVs) to inject the corrected gene into cells. These non-infectious viruses have been adapted for many gene therapies to date, and are also used in vaccines such as the AstraZeneca and J&J COVID-19 vaccines.
While they are very useful, a problem with AAV vectors is that they have historically not been selective enough at targeting specific cell types. For example, for muscular diseases high doses of this kind of therapy are needed for enough of a therapeutic gene to reach the muscle cells and this results in a large deposit of the viral vector in the liver. This can cause toxic effects and even deaths in some cases.
To try and combat this problem, Sharif Tabebordbar, PhD, a research scientist at the Broad, and colleagues modified AAV vectors to better target specific cell types, in this case muscle cells.
Writing in the journal Cell, the researchers describe their efforts to produce a new kind of AAV vector. Using a method called Directed Evolution of AAV capsids Leveraging In Vivo Expression of transgene RNA (DELIVER), developed by the group, they modified the outer shell of the AAV to make it more selective and able to specifically target muscle cells creating a new vector called MyoAAV.
They tested the new vector type in a mouse model of Duchenne muscular dystrophy, one of the more common genetic muscle diseases, and in a model of a rarer disease called X-linked myotubular myopathy. It was able to deliver therapeutic genes and also the CRISPR-Cas9 gene editing system directly to muscle cells and was 10-times more efficient at doing this than standard AAVs it was also effective at low doses.
The research team also tested the MyoAAV in non-human primates and in human muscle cells and found it was effective at delivering a therapeutic product in both.
“There have been many capsid engineering studies, which we’ve learned a lot from, but what we’ve done here is very comprehensive,” explained Tabebordbar in a press statement.
“We’ve evolved a family of capsids, found the mechanism by which it delivers genes, showed that this mechanism is conserved between species, and showed that we can provide a therapeutic benefit in animal models with an extremely low dose of the virus. Now we’re extremely excited about how this can be used to enable effective drug development for patients.”
While the first use of this technology is to better target muscle cells, the scientists believe their technique could also develop vectors to target other cell types for different genetic diseases.
“The DELIVER system described here provides a highly adaptable platform for identifying precise AAV capsid variants for any tissue or cell type in the body that could greatly expand the clinical and experimental applications of this vector system across fields and disciplines,” write the authors.
“We anticipate that adoption of DELIVER to additional tissue and organ systems will have a far-reaching impact in accelerating the development and translation of gene therapy and other genomic medicine approaches for a variety of human diseases.”
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