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Summary
A researcher with a personal mission to cure genetic muscle diseases has developed a more targeted and efficient approach to deliver healthy copies of defective genes in muscle cells.
As a teenager, Sharif Tabebordbar saw his father struggle with muscular dystrophy, a genetic condition that causes muscle loss over time. As his father weakened and eventually became unable to walk on his own, Tabebordbar decided he had to do something to help him.
Working in the laboratory of investigator Pardis Sabeti at the Howard Hughes Medical Institute at Harvard University, Tabebordbar has developed a targeted therapy that reverses the symptoms of muscular dystrophy in mice. This new method delivers gene therapy to muscle cells more accurately and efficiently than current approaches, the team reports on September 9, 2021 in the journal Cell.
“This system is clearly better than what we have now, and it will be exciting to see it go into the clinic,” says Jeffrey Chamberlain, a muscular dystrophy researcher at the University of Washington School of Medicine who was not involved. to work.
Muscular dystrophy is a group of diseases in which faulty genes trigger the constant breakdown of muscle tissue. Almost 20 years ago, when teenager Tabebordbar learned that a single gene was the root cause of most genetic muscle disease, he thought fixing it should be simple. “We know which gene is defective,” he says. “If we could just replace that gene, that would be it. So why is it taking so long?
Gene therapy seeks to solve genetic problems at their source. The technology was first used successfully in 1990 to treat a child with severe combined immunodeficiency (known as “bubble boy disease”). Today, not only can genes be replaced – as in treatments now used for inherited retinal diseases – but scientists are also testing CRISPR gene-editing technology to repair defective genes, such as those for sickle cell anemia. Gene therapy for muscular dystrophy, however, has encountered many obstacles, including how to effectively deliver it to muscles throughout the body.
As a graduate student at Harvard, Tabebordbar developed gene therapy in mice to repair Duchenne muscular dystrophy. During this time, he met two graduate students from MIT, Eric Wang and Albert Almada, who had family members with the disease, and they decided to work together. After completing his doctorate, Tabebordbar joined Editas Medicine, a gene editing company based in Cambridge, Massachusetts, to begin transferring his therapy to humans. Everything seemed to fall into place – and then he hit a roadblock. Most of the genes delivered ended up in the liver, he found, and not in the muscles, where they are needed.
Gene therapy delivers new genetic instructions to cells using harmless viruses, or pieces of viruses, that excel at getting into cells. As with many gene therapies, Tabebordbar chose to use an adeno-associated virus, or AAV, because it gets into cells without making people sick or triggering a strong immune response. But up to 90 percent of the virus infused into muscular dystrophy patients has traveled to the liver, where it can be toxic.
Tabebordbar realized he needed a better way to target the virus to the muscles. AAV is like a delivery vehicle for gene therapy, he says – and he needed better guidance. He decided to take advantage of the natural ability of viruses to evolve. Viruses frequently evolve to target host cells more effectively. In this case, Tabebordbar wanted to create viruses that concentrate on the muscles. This is where Sabeti, who studies viral evolution, could help.
In Sabeti’s lab, Tabebordbar and his colleagues discovered a promising family of AAVs with capsids, or protein envelopes, which specifically target muscle and heart cells. The team injected these viruses into mice and monkeys, then identified which ones best targeted muscle cells. They repeated this process to direct the evolution of AAV until they had a virus capable of effectively delivering gene therapy at doses as low as one-hundredth of those currently used in clinical trials. .
“It’s pretty amazing how well these viruses can adapt to target a very specific cell type,” Sabeti said.
The new capsids “appear to have benefits that are the best of both worlds,” says Chamberlain, who first reported that AAVs could be used to pass genes to muscles throughout the body in 2004. “They penetrate better in muscles and show a decreased propensity to enter the liver.
He notes that gene therapy for muscular dystrophy has yet to overcome other challenges that have arisen in clinical trials, such as avoiding attack by antibodies and effectively entering muscle stem cells, which help regenerate the muscle. muscle tissue. Still, he calls the improved delivery system “very promising”.
Tabebordbar is now working to test its new technologies in human trials.
Sabeti says she is proud of the way a team of students and technicians from her lab have come together around her project. “I think when people have this deep personal understanding of the importance of work, it can push them to do some pretty great things,” she says.
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Quote
Mohammadsharif Tabebordbar et al. “Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species.” ” Cell. Published online September 9, 2021. doi: 10.1016 / j.cell.2021.08.028
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