New Viral Vector Could Improve Gene Therapy for Muscle Diseases

Marisa Wexler MS avatar

by Marisa Wexler MS |

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A new viral vector that is better than conventional vectors — tools designed to deliver genetic material into cells — at targeting muscle cells may prove useful in developing a more effective gene therapy for muscular dystrophy (MD), according to researchers.

In fact, this new vector “is more than 10 times more efficient at reaching muscle than those currently used in clinical trials,” the scientists said in a news story.

The researchers described the new vector in the journal Cell, in a study titled “Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species.”

The general aim of gene therapy is to correct the genetic defect that causes a disease — for instance, delivering a non-mutated version of a gene to affected cells. This has commonly been done using a type of viral vector called an adeno-associated virus, or AAV, which can be manipulated in laboratories and doesn’t cause disease in people.

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The basic idea is that the now harmless virus can deliver an engineered genetic payload to the body’s cells, through a process called transduction. This process is similar to how viruses normally infect cells.

Designing AAV-based gene therapies for muscular dystrophy and other muscle diseases has been complicated because, to be effective, such therapies need to specifically target muscle cells. Often, the viral vector instead ends up in other tissues, particularly the liver, which can cause serious safety problems. In addition, according to the researchers, high doses of the gene-carrying virus are usually needed to reach the muscles throughout the body. Such high doses can have unwanted side effects.

“We know that if you get enough of the [gene therapy] into the target tissue, it’s going to be efficacious. It’s all about delivering a safe dose of the virus,” said Sharif Tabebordbar, PhD, a researcher at the Broad Institute of MIT and Harvard, in Massachusetts, and lead author of the study.

Tabebordbar has been working in this field for a decade, inspired by his father, who was diagnosed with a rare genetic muscle disease.

The biotechnology professor and his colleagues set out to design an AAV vector that could more effectively target muscle tissue. To do this, they devised a system called Directed Evolution of AAV capsids Leveraging In Vivo Expression of transgene RNA, or DELIVER.

In simple terms, the system involves starting with an established vector called AAV9, then generating a lot of different viral capsids, or shells, with small, random differences in their genetic code. These vectors then are injected into mice, and the researchers look at the muscle tissue to find vectors that are able to deliver their genetic cargo most effectively.

Specifically, the researchers looked for the expression of viral transgenes in muscle tissue — in other words, the extent that viral genetic material is being “read” by the cells. The viral capsids that were most successful were then taken for further selection and analysis.

“Our method is unique because we screened a wide array of capsids and used very stringent selection criteria,” Tabebordbar said. “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.”

The team selected one AAV capsid, which they dubbed MyoAAV 1A, for further testing. That showed that the vector was able to effectively deliver genetic information to muscle cells in mice, while delivery to the liver was notably reduced and no liver damage was found.

Further studies in a mouse model of Duchenne muscular dystrophy (DMD), the most common type of MD, further confirmed that MyoAAV 1A was able to effectively deliver genetic material to muscle cells.

Treated animals also showed greater strength. In a model of X-linked myotubular myopathy, MyoAAV 1A led to marked improvements in muscle function, weight, and survival at a viral dose up to 50 times lower than the one currently used in a clinical trial (NCT03199469), the researchers said.

Notably, MyoAAV 1A outperformed the original AAV9 vector, which is used in gene therapies that are currently in clinical testing.

Through additional structural analyses and rounds of selection, the researchers generated another vector — MyoAAV 2A — that was even more effective at transducing muscle cells. MyoAAV 2A outperformed both AAV9 and another vector being tested in clinical trials, AAVrh74, in a mouse model of DMD.

Further experiments showed that the DELIVER platform could be modified to generate viruses with the ability to target muscle cells in non-human primates (cynomolgus macaques). They also revealed the structural features that appear linked to the virus’ ability to get into muscle cells so effectively.

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Although the researchers specifically focused on muscle cells in this study, they noted that the DELIVER platform is “a comprehensive strategy for engineering and selecting effective AAV capsid variants for potent gene delivery into any tissue and/or cell type of interest.”

“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,” Tabebordbar said.

“Now we’re extremely excited about how this can be used to enable effective drug development for patients,” he said.

The advent of gene therapy in recent years has created new treatment possibilities for people with MD and other muscle diseases. Tabebordbar said his own father started having trouble walking when the researcher was a teenager, and eventually became wheelchair-bound.

“I watched my dad get worse and worse each day. It was a huge challenge to do things together as a family — genetic disease is a burden on not only patients but families. I thought: This is very unfair to patients and there’s got to be a way to fix this. That’s been my motivation during the 10 years that I’ve been working in the field of gene therapy,” he said.