Richard Horgan has waited for this moment for more than three years.
Last month, the Food and Drug Administration granted permission for his younger brother Terry, 27, who lives with muscular dystrophy, to receive a first-of-its-kind gene therapy that was tailor-made for his genetic mutation.
When the infusion of the drug happens at UMass Chan Medical School, it will be an emotional moment for Terry and Richard, the driving force behind the experimental drug.
The therapy, based on CRISPR gene editing, is designed to help Terry make the muscle proteins his body is missing. If it works, the approach could stabilize his condition, help him live longer, and possibly restore some of his sapped strength. The mutation that causes his disease is so rare, that he is likely the only person who will ever receive this therapy.
The Boston nonprofit behind the drug, Cure Rare Disease, was founded in 2017 by Richard Horgan, now 30, while he was still a student at Harvard Business School. By 2019 he had assembled a team of scientists at Charles River Laboratories, UMass Chan, Yale University, and other institutions to help design, test, and manufacture the bespoke therapy for his brother.
Cure Rare Disease said last week that the Food and Drug Administration had given a green light to its clinical trial. “We’re finally here,” Richard Horgan said. “We’re cautiously optimistic.”
The group will start the trial this year, he added. “We don’t have an exact date yet, but it should be soon.”
CRISPR gene editing, invented only a decade ago, is granting scientists the power to precisely alter DNA. Dozens of companies and academic labs are working with different versions of the technology to create one-and-done therapies that treat genetic diseases.
Nonetheless, the clinical trial for Terry’s therapy will mark multiple medical milestones: the first ever personalized CRISPR therapy; the first clinical trial of any gene editing therapy for muscular dystrophy; and the first clinical test of a new version of CRISPR that changes how a person’s cells interpret their genetic code, rather than changing the genetic code itself.
“It’s exciting,” Richard Horgan said, but added that he is “apprehensive to be the first to do any of these things.” To preserve some privacy for the family, he said that they would not be granting interviews during the trial, and that his brother was unavailable for comment.
“We’ll share the results when it’s ready and when it’s appropriate. But this is really going to be very emotionally intense. It’s not an unidentified patient,” Horgan added.
Other groups have undertaken similar collaborative efforts to make personalized genetic drugs — what scientists often call N-of-1 therapies, since they are designed for a single person.
In early 2018, Boston Children’s Hospital researcher Timothy Yu pioneered a custom treatment for a young girl, Mila Makovec, who was born with a fatal neurodegenerative disorder. For a time, the landmark therapy helped reduce Makovec’s seizures, but her disease was advanced, and she died in early 2021.
Dr. Taha Bali, a neurologist and a neuromuscular disorder expert at Tufts Medical Center who is not involved in the trial, said the idea of Terry’s custom therapy is “promising and bodes well for many other genetic diseases where there is a unique mutation and it’s hard to produce a therapy that works for all patients.”
But Bali also believes it’s important to “temper expectations.” Reversing the disease of someone in their 20s is an optimistic goal, he added. “I don’t know how obtainable that is at such a late stage.” Hoping for a treatment that stabilizes the disease and prevents it from getting worse is a “more realistic goal.”
Terry has long been too old to participate in the many clinical trials of genetic therapies for muscular dystrophy, which are generally limited to young boys. The unique cause of his disease means that some of those therapies wouldn’t help him anyway.
There are hundreds of mutations known to cause Duchenne muscular dystrophy, which almost exclusively affects males. These mutations prevent a crucial muscle protein called dystrophin from being made or result in only a partially effective protein. The result is greatly weakened muscles and, eventually, heart failure.
Terry’s condition is caused by a missing segment of DNA at the very beginning of his dystrophin gene. Curiously, all people, including Terry, have a backup copy of that code that is normally left unused in our muscles.
Monkel Lek, a scientist at Yale School of Medicine, devised a clever strategy using a version of CRISPR that coaxes Terry’s cells to use that backup code and restore his muscle protein. Charles River Labs conducted safety studies of the therapy in cells and in mice.
There are no FDA-approved CRISPR therapies, although the first one could come as soon as next year from Cambridge-based Crispr Therapeutics and Boston-based Vertex Pharmaceuticals.
The drug Terry Horgan will receive works differently from those being developed by local biotechs. Vertex and Crispr Therapeutics are making a treatment for genetic blood diseases in which a person’s blood stem cells are removed from their body, edited in the lab, and then reinfused. Experts caution that delivering the CRISPR technology directly into the body, as will be done for Terry, may be more challenging
Terry’s therapy relies on hollowed-out viruses to shuttle the CRISPR therapy into his cells, just like gene therapies. But the large dose of viruses needed to make this work can be dangerous.
Last year, Pfizer said that a young patient with Duchenne muscular dystrophy died in a clinical study of its experimental gene therapy for the disease. And last week STAT reported that two children have died from acute liver failure after receiving a commercial gene therapy sold by Novartis.
Before the drug is infused, Terry will take immunosuppressants to help minimize his body’s reaction to the viruses. He will then stay in the hospital for several days so doctors can monitor him for reactions such as liver failure or a runaway immune response. The therapy also carries unknown risks related to the novel CRISPR technology.
Richard Horgan hopes the therapy will halt any further decline in Terry’s strength. “And if we can see some improvement in cardiac and pulmonary functions, that will be awesome,” he added.
Over the past few years, Horgan’s non-profit has started developing therapies that could work for multiple patients whose diseases are so rare that they’ve been largely overlooked by the biotech industry.
Today, Cure Rare Disease is working on 19 other therapies based on multiple genetic technologies funded by donations from families, patient organizations, and companies.
Making these therapies is not cheap. Horgan estimates that each one will cost between $2.8 million and $3.5 million, with the bulk of the bill going toward producing the therapy.
Yet as high as that bill is, it underestimates the true cost of the the drug. Many scientists freely gave their time to the project, and industry partners worked at “significant discounts,” Horgan said.