Better gene transport system targets diseased muscle tissue – Harvard Gazette


When Sharif Tabebordbar was a teenager, his father began to have difficulty walking. Soon he became confined to a wheelchair and was diagnosed with a rare genetic muscle disease.

“I saw my father getting worse by the day,” Tabebordbar said. “It was a huge challenge doing things together as a family. “

For Tabebordbar, who is now a researcher at the Broad Institute at MIT and Harvard and an associate in the Department of Organic and Evolutionary Biology, the experience has led him to focus on gene therapy, and over the past decade has been his motivation to work in the field. “Genetic diseases are a burden not only on patients but on families,” he said. “I thought to myself, this is very unfair to the patients and there has to be a way to solve this problem.”

Together with colleagues at Broad and Harvard, Tabebordbar has moved closer to this goal with a new gene delivery system that has the potential to make gene therapy for muscle disease both safer and more effective for patients.

The system is called MyoAAV and is described in the journal Cell.

This is a new family of adeno-associated viruses that act as a better transport vehicle for gene therapy and can be used to transport a gene editing system sometimes referred to as CRISPR 2.0. In gene therapies for muscle disease, scientists often use harmless viruses known as adeno-associated viruses, to deliver a working copy of a pathogenic gene to cells that have shown promise in clinical trials. Therapies often face challenges as they require high doses of the virus carrying the gene to reach the cell and much of it ends up in the liver instead of muscle cells, which can lead to serious unwanted side effects or even death. died in some trials. participants.

In the study, the researchers show that the group of viral vectors they created are more than 10 times more effective at reaching and delivering therapy to muscle cells than other adeno-associated vectors currently used in clinical trials, avoiding largely the liver, and does so in doses about 100 to 250 times lower. For this reason, MyoAAV has the potential to better treat these conditions and reduce the risk of liver damage and other serious side effects.

Sharif Tabebordbar led the team of researchers that developed MyoAAV, a new family of viral vectors that could lead to safer gene therapies for genetic muscle diseases. Courtesy of Broad Communications

“We know that if you get enough of the drug into the target tissue it will be effective,” said Tabebordbar, who works in the lab of Pardis Sabeti, a fellow at the Broad Institute and a professor in the Harvard Organism Department. and evolutionary biology. “It’s about delivering a safe dose of the virus.”

Already, the system has delivered impressive results. The researchers used MyoAAV to transport therapeutic genes or the CRISPR-Cas9 gene editing system to muscle cells in mice and primates. They found that treatments delivered by the system improved muscle function in mouse models with Duchenne muscular dystrophy, the most common form of genetic muscle disease, and a rarer condition called X-linked myotubular myopathy. . The researchers also found that MyoAAV could efficiently deliver gene therapy to muscles of non-human primates and human muscle cells.

“All of these results demonstrate the wide applicability of MyoAAV vectors for delivery to muscle,” said lead study author Amy Wagers, professor and co-chair of Harvard’s Department of Stem Cells and Regenerative Biology and principal investigator at the Joslin Diabetes Center. “These vectors function in different disease models and across different ages, strains and species, demonstrating the robustness of this AAV family.”

The new study is a collaboration between researchers in the Department of Stem Cells and Regenerative Biology at Harvard, Broad and Boston Children’s Hospital.

The article details how the group modified the outer protein envelope of an adeno-associated viral capsid known as AAV9, a gene delivery vehicle commonly used in gene therapy, to improve its ability to transfer genes. in muscle cells. They then injected the capsids into mice and primates, then 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 with a unique surface structure that specifically targets muscle cells, and called them MyoAAV.

The researchers then put their capsids to the test: treating genetic muscle disease in animal models.

In the mouse model of Duchenne muscular dystrophy, which causes progressive muscle degeneration and weakness due to alterations in a protein that keeps muscles intact, MyoAAV carrying CRISPR-Cas9 led to more extensive repair of the dysfunctional gene in muscle tissue. This was compared to conventional AAV9 carrying the CRISPR components. Muscles from animals treated with MyoAAV also showed greater strength and function.

In collaboration with Alan Beggs’ lab at Boston Children’s Hospital, the research team showed that MyoAAV was also effective in treating Duchenne muscular dystrophy.

In the mouse model of X-linked myotubular myopathy, a fatal disease after about 10 weeks in mice, the researchers found that after receiving a dose 100 times lower than that of other viral vectors currently used in trials Clinically, all six mice treated with MyoAAV in the study lived as long as normal mice. In comparison, mice treated with AAV9 lived only to the age of 21 weeks.

In their final experiment, the team saw that MyoAAV designed for non-human primates delivered genes to the muscles of these animals much more efficiently than the natural capsids currently used in clinical trials. MyoAAV has also successfully introduced genes into human cells in the laboratory. The results suggest that MyoAAV can be used for muscle-directed gene delivery across different species, as various MyoAAV capsids used a similar mechanism to deliver genes to mouse and human muscle cells.

The next steps are to use the data from the study and examine how the system can be used to enable effective drug development for patients.

“We have a tremendous amount of information on this class of vectors from which the field can initiate many exciting new studies,” said Wagers.

Support for this research was provided in part by an anonymous philanthropic donation, the Howard Hughes Medical Institute, Sarepta Therapeutics, the Broad Institute’s Chemical Biology and Therapeutic Sciences program, the American Society of Gene & Cell Therapy, the National Institutes of Health, the Glenn Foundation, the Muscular Dystrophy Association USA, and the Anderson Family Foundation.


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