Is this the ticket to gene therapy for muscle diseases?
by June Kinoshita, Director of Research and Patient Engagement
A lot of emails cross my desk every day, but one that came last September from an FSHD patient pulled me right down a rabbit hole that proved to be fantastic. It was a story from the famous Harvard-MIT Broad Institute in Cambridge, MA, about a researcher who had harnessed a method called “directed evolution” to engineer special viruses that improved the efficiency of targeting gene therapies to skeletal muscle while limiting liver exposure, thereby reducing the toxic side effects frequently reported in gene therapy trials. Not only was the research a tour de force, but the scientist leading the charge, Sharif Tabebordbar, was inspired by his father’s battle with an unspecified “rare genetic muscle disease.”
Current gene therapy relies on a family of viruses called adeno-associated virus-9 (AAV9), which are adept at getting into cells to deliver the therapeutic “genetic fix.” However, one of the limitations of AAV9 is the non-specific delivery to different cell types. To treat diseases of muscle—which make up 40 percent of the body—one needs to inject enormous amounts of AAV9, but most of the virus end up not in muscle but in the liver, where it can reach dangerous levels. Some gene therapy trials had to be halted following patients’ deaths from liver damage. To address this shortcoming, many groups have sought to improve the efficiency of muscle delivery by testing different AAV9 sub-types. Although some improvements have been gained, liver exposure using these methods have only shown marginal benefits and toxicity remains a major concern.
To solve this problem, Tabebordbar embarked on a bold experiment to alter the virus’s outer protein coat, called the capsid, so that it prefers muscle and avoids the liver. He and his team added random amino acids to the part of the AAV9 capsid that binds to cells. They made millions of varieties, injected them into mice and monkeys and isolated the ones that successfully entered and delivered therapeutic genes to muscle cells. They called this muscle-fancying virus MyoAAV.
Next, working with Alan Beggs of Boston Children’s Hospital, Tabebordbar’s team tested MyoAAV in mouse models of a genetic disease called X-linked myotubular myopathy (XLMTM), which is usually fatal in childhood. In his NIH director’s blog, Francis Collins described what happened. “The XLMTM mice normally die in 10 weeks. But, after receiving MyoAAV carrying a corrective gene, all six mice had a normal lifespan. By comparison, mice treated in the same way with traditional AAV9 lived only up to 21 weeks of age. What’s more, the researchers used MyoAAV at a dose 100 times lower than that currently used in clinical trials.”
Additional experiments showed that MyoAAVs also work in human muscle cells in a lab dish. These results, published in the top-line journal Cell, combined with the compelling personal story, garnered a glowing profile in the New York Times.
Excited by the research and curious to know more about the back story, we reached out directly to Tabebordbar. He told us his father’s mysterious ailment was indeed FSHD. He recalled growing up in Iran, how his father started to have problems with his balance. How the weakness spread through his body until he could no longer walk unaided. Today he needs a wheelchair and must use one hand to lift the other—a gesture familiar to many who share this diagnosis.
“I watched my dad get worse and worse each day,” Tabebordbar recalled. “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.”
We inquired whether Tabebordbar knew whether he had inherited FSHD from his father. He said he had himself tested and learned that, in a most unlikely reshuffling of the genetic deck, he had inherited the shortened D4Z4 region but not the “permissive” polyA section that is needed to stabilize the DUX4 messenger RNA. “Lucky” would be a vast understatement of how he dodged having FSHD himself.
What happens next? Tabebordbar said he hopes to develop gene therapies for a variety of muscle diseases. Should FSHD be one of the diseases chosen, we discussed how the FSHD Society can support these efforts, by pushing for validation of biomarkers and clinical outcomes for gene therapy clinical trials, engaging patients and families on the design of future trials and continuing our investment in the FSHD Clinical Trial Research Network.
The impact of Tabebordbar’s work may reach far beyond muscle diseases, as the directed evolution approach could in principle be used to generate AAVs with preferences for other organs in the body. “With this latest advance,” said NIH’s Francis Collins, “the hope is that the next generation of promising gene therapies might soon make its way to the clinic to help Tabebordbar’s father and so many other people.”
Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Tabebordbar M, Lagerborg KA, Stanton A, King EM, Ye S, Tellez L, Krunnfusz A, Tavakoli S, Widrick JJ, Messemer KA, Troiano EC, Moghadaszadeh B, Peacker BL, Leacock KA, Horwitz N, Beggs AH, Wagers AJ, Sabeti PC. Cell. 2021 Sep 4:S0092-8674(21)01002-3.
He Can’t Cure His Dad. But a Scientist’s Research May Help Everyone Else (NY Times)
Engineering a Better Way to Deliver Therapeutic Genes to Muscles (NIH)
A new gene-delivery vehicle could make gene therapy for muscle diseases safer and more effective (Broad Institute)