Muscular dystrophy gene therapy nears approval, but safety concerns linger | Science

Five years ago, when Duchenne muscular dystrophy (DMD) began making it hard for him to walk, 7-year-old Conner Curran received a blood infusion of trillions of viruses carrying a muscle gene to replace his mutant one. Within 2 months the Connecticut boy went from crawling up stairs to “flying up,” says his mother, Jessica Curran. The family and the researchers hoped he would never need another gene infusion. But the experimental treatment’s effects are already fading.

Conner’s story sums up the mixture of hope and disappointment among families and researchers as gene therapy for DMD, long seen as a potential cure for the debilitating and ultimately fatal disease, reaches a key milestone. This week, the U.S. Food and Drug Administration (FDA) was expected to approve a treatment similar to Conner’s, developed by Sarepta Therapeutics.

But the therapy barely squeaked by an FDA advisory panel, with many members unconvinced that it works. Although “it’s gratifying to see something approved after all these years, the current system is not perfect by any means,” acknowledges muscular dystrophy researcher Jeffrey Chamberlain of the University of Washington, who helped lay the groundwork for the new gene therapies.

As a result, researchers are working on improvements, including strategies to give repeated doses to DMD patients like Conner and to edit the mutant disease gene with CRISPR instead of replacing it. They are also grappling with a major, unpredictable safety issue for some patients: toxicity from the high doses of the supposedly benign adeno-associated viruses (AAVs) used to deliver genetic treatments into muscle cells.

Last year, a young man with DMD died days after being given AAVs to ferry the DNA for CRISPR into his muscles and heart, and the virus has now been suspected or implicated in at least 11 previous gene therapy deaths, including a second DMD patient. “It’s clear we’ve passed the maximally tolerated single dose” of AAV, says gene therapy researcher Barry Byrne of the University of Florida. Companies and labs are therefore trying to suppress the body’s immune response to AAVs, which might decrease the risks of large doses or allow smaller, repeat doses. Immunosupression could also let previously treated patients “benefit from new, even better AAV therapies,” says muscular dystrophy researcher Melissa Spencer of the University of California, Los Angeles (UCLA).

Because of a mutation in the gene for dystrophin, DMD patients lack functioning copies of the huge protein that serves as a shock absorber inside muscle fiber cells. Without it, muscle cells become damaged and gradually die. Patients usually end up using a wheelchair by age 12 and succumb to heart or respiratory problems by age 30. (Most are boys; the dystrophin gene is on the X chromosome, so girls have two copies and rarely develop DMD.) Existing therapies are only modestly effective.

The DNA encoding dystrophin is too large to package into the AAVs widely used in gene therapy. But inspired by an older man who was missing nearly half of the protein yet had only mild muscular dystrophy, Chamberlain’s lab 2 decades ago devised a gene for a miniature dystrophin. Puppies with a version of DMD grew up with near normal muscle function when given this gene. Sarepta and three other companies, Pfizer (which treated Conner Curran), Solid Biosciences, and Généthon, went on to test delivering a micro- or minidystrophin gene into the muscles of young boys. Patients typically receive a one-time infusion of 1 x 10¹⁴ AAVs per kilogram of body weight, among the largest doses for any gene therapy.

At a 12 May FDA advisory meeting to consider Sarepta’s request for approval of its gene therapy under an “accelerated” pathway, agency staff and outside advisers were skeptical largely because the company didn’t have clear data confirming the intervention worked better than a placebo or that levels of microdystrophin in the boy’s muscles correlated with better muscle function. In the end, however, the advisory committee voted eight to six in favor of the therapy, which under an accelerated approval could be sold until a larger trial already underway is completed. If that study fails to definitively show benefits, the treatment could be pulled from the market. An FDA decision was expected by 29 May.

Even if the treatment proves to work, researchers now expect its effects to wear off. The AAV does not integrate the replacement gene into a cell’s genome, instead delivering it into the nucleus as a loop of DNA. As damaged muscle fiber cells are being repaired by dividing muscle stem cells, some will not inherit the loop, and the benefits will fade as the modified cells become outnumbered.

Jessica Curran says this appears to be happening to Conner: Last fall, the sixth grader began using an electric scooter to conserve his strength in long school hallways. UCLA neurologist Perry Shieh, who is seeing declines in DMD patients he’s treated in the Sarepta, Pfizer, and Solid trials, says, “The parents are asking: ‘What is next for my child?’”

For now, the answer is nothing because the boys make antibodies to AAV that would block any effort to retreat them the same way. But companies and academic researchers are trying to remove these antibodies with blood-filtering machines and drugs. They are also testing using other drugs to suppress immune cells that recognize AAVs or that make antibodies targeting the viruses.

“There are many overlapping, complementary strategies” that would allow AAV redosing, Byrne says. His group will soon launch a small study to see whether AAV antibodies can be lowered enough in Conner Curran and other DMD gene therapy patients to potentially allow them to be retreated. Although these immunosuppressive approaches carry their own risks, “compared to the consequences of disease … we feel it’s justified,” Byrne says.

Preventing a patient’s immune system from making antibodies to an initial dose of AAV gene therapy might also make it possible to exchange a single large dose for smaller, repeat doses. An analysis of the October 2022 death of Terry Horgan, a 27-year-old DMD patient who received a custom-made CRISPR treatment designed to switch on a gene, underscored the need to reduce risks. Last week, a team of researchers, funded by the nonprofit his family had established to treat DMD and other diseases, posted a preprint on medRxiv absolving the gene editor and instead suggesting that the AAV he was given was toxic to his lungs and atrophied heart.

There’s hope that CRISPR-based DMD gene therapies can eventually sidestep the AAV issue. Some teams are trying to use the same lipid nanoparticles, or fat bubbles, employed in the messenger RNA COVID-19 vaccines as a delivery vehicle for RNA encoding the gene editor’s molecular components. But until researchers figure out how to steer the fat bubbles to muscle cells, AAV remains the only proven option for targeting the tissue.

Even if delivered by AAVs, CRISPR could still prove a better solution than current approaches that introduce a new dystrophin gene. For example, the gene editor could be used in some patients to “repair” the existing dystrophin gene in muscle cells by snipping out a sequence that causes cells to misread it. The gene would then produce nearly full-length dystrophin driven by natural promoters so it’s made “at the right time, in the right place,” notes molecular biologist Eric Olson of the University of Texas Southwestern Medical Center. And if the CRISPR therapy edits muscle stem cells, the changed gene should persist and its effects could be long-lasting.

Olson’s approach, which his lab has demonstrated in mice and dogs, is under development by Vertex Pharmaceuticals. It hopes to start a clinical trial later this year. “The work is progressing well,” Olson says.

CRISPR has its own downsides, however. The DNA-snipping Cas9 protein, one of its two components, comes from bacteria and can trigger an immune reaction against edited cells. As a result, “Your treated cells will be eliminated,” says gene therapy researcher Dongsheng Duan of the University of Missouri School of Medicine, whose lab showed this phenomenon 2 years ago in dogs that got CRISPR for their DMD. Efforts are now underway to design Cas9 to be less immunogenic or to be quickly eliminated from cells after it makes the needed DNA cut.

For now, Spencer welcomes the expected approval of Sarepta’s gene therapy. “We have to start somewhere. This approval is going to help move the field forward,” she says. Eventually, we’ll have improved therapies.”

Jessica Curran hopes those improvements will come soon, and make it possible for her son to get another gene boost. “We have to figure out this antibody issue,” she says. “Because these kids are all going to need [gene therapy] again.”

Five years ago, when Duchenne muscular dystrophy (DMD) began making it hard for him to walk, 7-year-old Conner Curran received a blood infusion of trillions of viruses carrying a muscle gene to replace his mutant one. Within 2 months the Connecticut boy went from crawling up stairs to “flying up,” says his mother, Jessica Curran. The family and the researchers hoped he would never need another gene infusion. But the experimental treatment’s effects are already fading.

Conner’s story sums up the mixture of hope and disappointment among families and researchers as gene therapy for DMD, long seen as a potential cure for the debilitating and ultimately fatal disease, reaches a key milestone. This week, the U.S. Food and Drug Administration (FDA) was expected to approve a treatment similar to Conner’s, developed by Sarepta Therapeutics.

But the therapy barely squeaked by an FDA advisory panel, with many members unconvinced that it works. Although “it’s gratifying to see something approved after all these years, the current system is not perfect by any means,” acknowledges muscular dystrophy researcher Jeffrey Chamberlain of the University of Washington, who helped lay the groundwork for the new gene therapies.

As a result, researchers are working on improvements, including strategies to give repeated doses to DMD patients like Conner and to edit the mutant disease gene with CRISPR instead of replacing it. They are also grappling with a major, unpredictable safety issue for some patients: toxicity from the high doses of the supposedly benign adeno-associated viruses (AAVs) used to deliver genetic treatments into muscle cells.

Last year, a young man with DMD died days after being given AAVs to ferry the DNA for CRISPR into his muscles and heart, and the virus has now been suspected or implicated in at least 11 previous gene therapy deaths, including a second DMD patient. “It’s clear we’ve passed the maximally tolerated single dose” of AAV, says gene therapy researcher Barry Byrne of the University of Florida. Companies and labs are therefore trying to suppress the body’s immune response to AAVs, which might decrease the risks of large doses or allow smaller, repeat doses. Immunosupression could also let previously treated patients “benefit from new, even better AAV therapies,” says muscular dystrophy researcher Melissa Spencer of the University of California, Los Angeles (UCLA).

Because of a mutation in the gene for dystrophin, DMD patients lack functioning copies of the huge protein that serves as a shock absorber inside muscle fiber cells. Without it, muscle cells become damaged and gradually die. Patients usually end up using a wheelchair by age 12 and succumb to heart or respiratory problems by age 30. (Most are boys; the dystrophin gene is on the X chromosome, so girls have two copies and rarely develop DMD.) Existing therapies are only modestly effective.

The DNA encoding dystrophin is too large to package into the AAVs widely used in gene therapy. But inspired by an older man who was missing nearly half of the protein yet had only mild muscular dystrophy, Chamberlain’s lab 2 decades ago devised a gene for a miniature dystrophin. Puppies with a version of DMD grew up with near normal muscle function when given this gene. Sarepta and three other companies, Pfizer (which treated Conner Curran), Solid Biosciences, and Généthon, went on to test delivering a micro- or minidystrophin gene into the muscles of young boys. Patients typically receive a one-time infusion of 1 x 10¹⁴ AAVs per kilogram of body weight, among the largest doses for any gene therapy.

At a 12 May FDA advisory meeting to consider Sarepta’s request for approval of its gene therapy under an “accelerated” pathway, agency staff and outside advisers were skeptical largely because the company didn’t have clear data confirming the intervention worked better than a placebo or that levels of microdystrophin in the boy’s muscles correlated with better muscle function. In the end, however, the advisory committee voted eight to six in favor of the therapy, which under an accelerated approval could be sold until a larger trial already underway is completed. If that study fails to definitively show benefits, the treatment could be pulled from the market. An FDA decision was expected by 29 May.

Even if the treatment proves to work, researchers now expect its effects to wear off. The AAV does not integrate the replacement gene into a cell’s genome, instead delivering it into the nucleus as a loop of DNA. As damaged muscle fiber cells are being repaired by dividing muscle stem cells, some will not inherit the loop, and the benefits will fade as the modified cells become outnumbered.

Jessica Curran says this appears to be happening to Conner: Last fall, the sixth grader began using an electric scooter to conserve his strength in long school hallways. UCLA neurologist Perry Shieh, who is seeing declines in DMD patients he’s treated in the Sarepta, Pfizer, and Solid trials, says, “The parents are asking: ‘What is next for my child?’”

For now, the answer is nothing because the boys make antibodies to AAV that would block any effort to retreat them the same way. But companies and academic researchers are trying to remove these antibodies with blood-filtering machines and drugs. They are also testing using other drugs to suppress immune cells that recognize AAVs or that make antibodies targeting the viruses.

“There are many overlapping, complementary strategies” that would allow AAV redosing, Byrne says. His group will soon launch a small study to see whether AAV antibodies can be lowered enough in Conner Curran and other DMD gene therapy patients to potentially allow them to be retreated. Although these immunosuppressive approaches carry their own risks, “compared to the consequences of disease … we feel it’s justified,” Byrne says.

Preventing a patient’s immune system from making antibodies to an initial dose of AAV gene therapy might also make it possible to exchange a single large dose for smaller, repeat doses. An analysis of the October 2022 death of Terry Horgan, a 27-year-old DMD patient who received a custom-made CRISPR treatment designed to switch on a gene, underscored the need to reduce risks. Last week, a team of researchers, funded by the nonprofit his family had established to treat DMD and other diseases, posted a preprint on medRxiv absolving the gene editor and instead suggesting that the AAV he was given was toxic to his lungs and atrophied heart.

There’s hope that CRISPR-based DMD gene therapies can eventually sidestep the AAV issue. Some teams are trying to use the same lipid nanoparticles, or fat bubbles, employed in the messenger RNA COVID-19 vaccines as a delivery vehicle for RNA encoding the gene editor’s molecular components. But until researchers figure out how to steer the fat bubbles to muscle cells, AAV remains the only proven option for targeting the tissue.

Even if delivered by AAVs, CRISPR could still prove a better solution than current approaches that introduce a new dystrophin gene. For example, the gene editor could be used in some patients to “repair” the existing dystrophin gene in muscle cells by snipping out a sequence that causes cells to misread it. The gene would then produce nearly full-length dystrophin driven by natural promoters so it’s made “at the right time, in the right place,” notes molecular biologist Eric Olson of the University of Texas Southwestern Medical Center. And if the CRISPR therapy edits muscle stem cells, the changed gene should persist and its effects could be long-lasting.

Olson’s approach, which his lab has demonstrated in mice and dogs, is under development by Vertex Pharmaceuticals. It hopes to start a clinical trial later this year. “The work is progressing well,” Olson says.

CRISPR has its own downsides, however. The DNA-snipping Cas9 protein, one of its two components, comes from bacteria and can trigger an immune reaction against edited cells. As a result, “Your treated cells will be eliminated,” says gene therapy researcher Dongsheng Duan of the University of Missouri School of Medicine, whose lab showed this phenomenon 2 years ago in dogs that got CRISPR for their DMD. Efforts are now underway to design Cas9 to be less immunogenic or to be quickly eliminated from cells after it makes the needed DNA cut.

For now, Spencer welcomes the expected approval of Sarepta’s gene therapy. “We have to start somewhere. This approval is going to help move the field forward,” she says. Eventually, we’ll have improved therapies.”

Jessica Curran hopes those improvements will come soon, and make it possible for her son to get another gene boost. “We have to figure out this antibody issue,” she says. “Because these kids are all going to need [gene therapy] again.”