AAV Capsid Variants that Better Target Muscle Developed

Researchers at the Broad Institute of MIT and Harvard and Harvard University have developed a new family of adeno-associated viruses (AAVs) that improve targeting of the muscle tissue. This group of viral vectors, which the researchers call MyoAAV, is reportedly more than 10 times more efficient at reaching muscle than those currently used in clinical trials and largely avoids the liver. The team showed that, because of this increased efficiency, MyoAAV can be used to deliver therapeutic genes at around 100 to 250 times lower doses than other viral vectors used in other studies and trials, potentially reducing the risk of liver damage and other serious side effects.

In the study published today in Cell, Sharif Tabebordbar, first author of the paper, and collaborators describe how they modified the outer protein shell of AAV, known as the capsid, to create MyoAAV. They did this using a method they developed called Directed Evolution of AAV capsids Leveraging In Vivo Expression of transgene RNA (DELIVER).

The team started with AAV9, and used DELIVER to improve its ability to shuttle genes into muscle cells. The researchers first generated millions of different AAV capsids by adding random strings of amino acids to the portion of the AAV capsid that is exposed on the surface of the virus and binds to cells. They then injected the capsids into mice and non-human primates and sampled and sequenced muscle tissue throughout the body to look for the capsids that had successfully delivered their genetic cargo. They found a family of capsid variants—MyoAAV—with a unique surface structure that specifically targets muscle cells and used MyoAAV for the next step: attempting to treat genetic muscle disease in animal models.

Using MyoAAV, the researchers delivered either therapeutic genes or the CRISPR-Cas9 gene-editing system specifically to muscle cells. They improved muscle function in mouse models of Duchenne muscular dystrophy and of a rarer disease called X-linked myotubular myopathy. The researchers also found that MyoAAV can effectively deliver gene therapies to muscle in nonhuman primates and to human muscle cells.

“Our method is unique because we screened a wide array of capsids and used very stringent selection criteria. We wanted to find capsids that could not only physically enter the cell, but also proceed through different steps of transduction and express their transgenes,” said Tabebordbar.