CAMBRIDGE, Massachusetts—On the 4th floor of a sleek new office building in the heart of suburban Boston’s “innovation hub,” the 149 employees of Generation Bio are racing to develop redosable gene therapies for hemophilia and other rare diseases that currently have no cure.
Doug Kerr, MD, PhD, is Generation Bio’s chief medical officer. A neurologist by profession, Dr. Kerr is best known for his work at Biogen—headquartered one city block away—where he led the development of nusinersen (Spinraza®) for the treatment of spinal muscular atrophy (SMA).
At Generation Bio, which was founded in 2016, Dr. Kerr heads up efforts to “create the next generation of gene therapy” that will enable the redosable, durable expression of proteins missing in patients with specific genetic diseases such as hemophilia A.
“We’ve seen amazing advances with essentially first‑generation gene therapies, namely [adeno-associated virus (AAV)], but they are one‑time therapies,” he said. “You can only give that therapy once. When you’re correcting a genetic disease, you’ve only got one shot. You’ve got to get it right at the first dose.”
Dr. Kerr, speaking to Rare Disease Advisor during our September 2021 visit to Generation Bio’s office and laboratory, said that, with AAV, if a patient doesn’t receive the correct dose the first time, nothing can be done about it.
“Individuals are different, and not everybody responds in the same way to that dose,” he said, explaining the company’s goal is to find a way to deliver gene therapy with the durability of AAV, but also with the ability to tailor that dosage for individual patients.
That way, he said, “if you don’t get it on the first dose, that’s OK. You can go back and do it again. That is a fundamental shift from how gene therapy is currently considered.”
Dr. Kerr added: “It also turns out that AAV, although the expression of the corrected transgene is long-lived, it’s not permanent. It’s not forever. We see that in individuals with hemophilia [who receive] AAV gene therapy, the expression wanes over time. What you need in order to be able to give lifelong benefit is the opportunity to redose, if and when expression wanes.”
For years, hemophilia patients have depended on enzyme replacement therapy to keep their disease in check. But that may soon be changing.
“Lots of advances have been made in hemophilia back from the days, decades ago, when individuals had to be administered recombinant factors that were very short-lived. They had very short half‑lives. You had to administer intravenously factor 3 to 5 to 7 times per week,” he said.
“Over the last 15 years or so, long‑acting factors have been developed that can confer hemostasis, meaning the ability to clot, given once or twice or three times a week. But that still is a massive burden to hemophilia patients. And it’s not perfect because even after they’ve been administered recombinant factor, you still can bleed in some situations such as a car accident, surgery, or a fall,” he explained.
“So what if you could give a gene therapy that chronically administers into the blood sufficient factor VIII to prevent bleeding in virtually all considerations, under any circumstances? It would be really amazing for patients to essentially be able to forget that they’ve got the disease. That’s what we’re working toward.”
The technology offers particular promise for hemophiliacs as well as patients with phenylketonuria (PKU), Gaucher disease, Wilson disease, and Stargardt macular degeneration.
Dr. Kerr said Generation Bio is investing heavily in a proprietary nonviral genetic medicine platform that focuses on 3 core elements: closed-ended DNA (ceDNA), which enables the durable expression of transgenes and expression of large genetic payloads; cell-targeted LNP (ctLNP), which allows redosable delivery to multiple tissues; and enzymatic manufacturing.
“What are the advantages of that approach? First, that DNA is very pure. We know exactly what it is, and it’s very pure,” he said. “Second, we can get this very quickly. We don’t have to wait weeks and months for cells to produce the ceDNA. We can literally make it in a day. Third, we can make lots of it. We believe, using this system, you can make tens of millions, hundreds of millions of doses at scale.”
Specifically for patients with hemophilia, a big disadvantage of AAV gene therapy is that it can only be administered once all the body’s cells have stopped dividing, or about the age of 18—even though hemophilia often starts in the first decade of life.
“With our redosable gene therapy, you can go right at the onset of disease. As the tissue and the body grows, you may need another dose to keep up with that growth and have enough factor VIII levels in the body. It may be more frequently during childhood and adolescence, but that’s OK, we’ll redose,” Dr. Kerr said.
“Then, once you get to adulthood, you may need it every 3-5 years. That allows you to go at the onset of disease, maybe preventing all bleeds and enable the patient to truly forget that they’ve got hemophilia.”
At present, Generation Bio is in the preclinical phase; no clinical trial testing is being done at this point and it’ll stay that way for a while. Yet Dr. Kerr said all the patient advocacy groups he’s spoken to have indicated the urgency of something beyond AAV-based gene therapy.
“There is still huge unmet need in hemophilia, and much of that unmet need cannot be met by the first‑generation gene therapies,” he said. “But we don’t want to raise expectations too high too soon. This community has been through a lot, and we want to be very careful about how we earn the trust of this community going forward.”