A researcher with a personal mission to cure genetic muscle diseases has developed a more targeted and effective approach for delivering healthy copies of faulty genes into muscle cells.
As a teenager, Sharif Tabebordbar watched his father struggle with muscular dystrophy, a genetic disease that causes muscle loss over time. As his father grew weaker and eventually unable to walk on his own, Tabebordbar decided he had to do something to help.
Working in Howard Hughes Medical Institute Investigator Pardis Sabeti’s lab at Harvard University, Tabebordbar has developed a targeted therapy that reverses symptoms of muscular dystrophy in mice. This new method delivers gene therapy to muscle cells more precisely and efficiently than current approaches do, the team reports 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 move into the clinic,” says Jeffrey Chamberlain, a muscular dystrophy researcher at the University of Washington School of Medicine who was not involved with the work.
Muscular dystrophy is a group of diseases in which defective genes trigger the constant breakdown of muscle tissue. Nearly 20 years ago, when the teenaged Tabebordbar learned that just one gene was at the root of most genetic muscle diseases, he thought fixing it should be simple. “We know what gene is defective,” he says. “If we can just replace that one gene, that would be it. So why is it taking so long?”
Gene therapy seeks to fix genetic problems at their source. The technology was first successfully used 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 in sickle cell disease. Gene therapy for muscular dystrophy has faced numerous obstacles, though, including how to deliver it efficiently into muscles throughout the body.
As a graduate student at Harvard, Tabebordbar developed a gene therapy in mice to repair Duchenne muscular dystrophy. During this time, he met two MIT graduate students, Eric Wang and Albert Almada, who had family members with the disease, and they decided to collaborate. After finishing his PhD, Tabebordbar joined Editas Medicine, a gene editing company based in Cambridge, Massachusetts, to start moving his therapy to humans. Everything seemed to be coming together – and then he hit a roadblock. Most of the delivered genes were ending up in the liver, he discovered, not in the muscles, where it’s needed.
Gene therapy delivers new genetic instructions to cells using harmless viruses, or pieces of viruses, which excel at entering cells. As with many gene therapies, Tabebordbar had chosen to use an adeno-associated virus, or AAV, because it enters cells without making people sick or triggering a strong immune response. But up to 90 percent of the virus infused into patients for muscular dystrophy traveled to the liver, where it can be toxic.
Tabebordbar realized that he needed a better way to target the virus to muscle. AAV is like a delivery vehicle for gene therapy, he says – and it needed improved directions. He decided to take advantage of viruses’ natural ability to evolve. Viruses frequently evolve to target host cells more effectively. In this case, Tabebordbar wanted to create viruses that home in on muscles. That’s where Sabeti, who studies viral evolution, could help.
In Sabeti’s lab, Tabebordbar and colleagues found a promising family of AAVs with capsids, or protein shells, that specifically target muscle and heart cells. The team injected mice and monkeys with these viruses, and then tracked which ones best targeted muscle cells. They repeated this process to direct the evolution of the AAV until they had a virus that could effectively deliver gene therapy at doses as low as a hundredth of those currently used in clinical trials.
“It’s pretty amazing to see how exquisitely these viruses can adapt to target a very specific cell type,” Sabeti says.
The new capsids “seem to have advantages that are the best of both worlds,” says Chamberlain, who first reported that AAVs could be used to deliver genes to muscles throughout the body in 2004. “They get into muscle better, and they show a reduced propensity to get into the liver.”
He notes that gene therapy for muscular dystrophy must still overcome other challenges that have arisen in clinical trials, such as avoiding attack by antibodies and efficiently getting into muscle stem cells, which help regenerate muscle tissue. Still, he calls the improved delivery system “very promising.”
Tabebordbar is now working toward testing his new technologies in human trials.
Sabeti says she’s proud of how a team of students and technicians in her laboratory came together around his project. “I think that when people have this deep personal understanding of the importance of the work, it can move them to do pretty tremendous things,” she says.
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