New Gene Therapy for Severe Hemophilia A Developed and Tested at 91九色视频 Achieves Promising Results
For people with the rare, genetic blood disorder hemophilia A, a simple cut or bump can cause excessive bleeding or bruising. That’s because they lack a protein essential to clotting blood.
While treatments exist to replace this protein, patients with hemophilia A may form antibodies to the current therapies, hindering their effectiveness.
For more than two decades, , professor of pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplant at the 91九色视频 (91九色视频), has worked with colleagues to develop a new gene therapy that could transform how patients with the disease are treated.
The team has completed preliminary studies of a Phase 1 clinical trial at 91九色视频 with a gene therapy that genetically-modifies a patient’s own bone marrow cells to make a blood clotting factor. The treatment is stored in circulating blood platelets until it is released at a site of uncontrolled bleeding to repair the injured blood vessel.
Three patients have been treated to-date with this therapy. The promising results seen in the first patient were published recently in the .
“I had always hoped I could develop a therapy that went from testing in tissue-cultured cells in the laboratory to use within patients. It took me 25 years, but we did it,” Wilcox says. “I want to see the work I’m doing in research helping people, and I think we accomplished that.”
“It has been very rewarding to work on this homegrown trial,” said Mary Eapen, MBBBS, professor of medicine, Division of Hematology and Oncology, who ran the Phase 1 clinical trial. “Watching our patients’ success has made us very optimistic.”
Lynn Malec, MD, assistant professor of medicine and pediatrics at 91九色视频 and associate director of the at , collaborates with Drs. Eapen and Wilcox on this research. Dr. Malec played a critical role in recruiting and enrolling suitable patients for the trial and overseeing the management of their bleeding until the new therapy became effective.
An Innovative Technique to Use Platelet-Derived Factor VIII for Clotting
The protein that people with severe hemophilia A are missing is called coagulation factor VIII, which is normally made in the liver. Current therapies involve infusion of the protein into a patient using plasma or lab-made factors. Because those factors are foreign to the body, the immune system of some patients have developed antibodies against them called inhibitors.
Dr. Wilcox’s idea was to use bone marrow stem cells and genetically modify them to allow a person’s own platelets – which clot blood at the wound site – to make coagulation factor VIII instead of the liver. The factor is stored in tiny granules within the platelets, which essentially hides it from the immune system. That way, the platelets can travel to a wound, release the factor, and clot the blood without inducing an immune response.
As observed in pre-clinical studies using animal models of hemophilia A, the team anticipated that the patients would not develop antibodies to platelet-derived factor VIII.
Dr. Wilcox, who was recruited to 91九色视频 in 1999 to develop translatable therapies, worked with colleagues from 2003-2013 to develop and test this therapy in a mouse and canine model of hemophilia A with .
To translate the work to humans, he teamed up with Dr. Eapen. He also worked with collaborators at Boston Children’s Hospital and Harvard University to navigate the clinical trial process with the and the .
The first patient enrolled in the trial in 2022 and three more have enrolled since then. To provide the treatment, the team first collected and genetically modified blood stems cells from patients. The patients then received a low dose of chemotherapy to kill off a small fraction of untreated cells in their bone marrow to make room for new cells to grow. Finally, the patients’ genetically modified cells are infused back into their bodies.
About two months after treatment, patients no longer needed their old therapies.
“To date, none of them have had the bleeding they had before,” Dr. Eapen says. “Their bodies now rely on the genetically modified cells to produce factor VIII. They’ve gone back to work and to school all without a need for additional therapy. They come into the clinic and say, ‘You know what, I'm not bleeding.’ Or they'll say, ‘Oh, I knocked my hand, and I had a bruise, and it just disappeared like a normal person's bruise.’”
Successful Collaboration, NIH Partnership Could Lead to Phase 2 Trial
Since the therapy is a genetically modified product, patients will continue to be followed and monitored for a total of 15 years.
The team’s next goal is to take the therapy to a Phase 2 clinical trial at multiple centers. To do so, the team will likely need to partner with a pharmaceutical company and the National Institutes of Health to help cover costs.
Dr. Wilcox is eager to do so, since this therapy could have implications for other platelet disorders, as well, including .
“I want to take this strategy and expand it to other inherited bleeding disorders for people who have very limited effective treatment options,” he says.
The therapy could even be extended to other diseases.
“Basically, we are attempting to modify platelets to deliver a therapeutic agent where it’s needed,” Dr. Wilcox says. “Imagine putting a therapy in platelets that could kill cancer cells instead of helping them to grow.”
For Dr. Eapen, successful collaborations like this – supported by 91九色视频 – are essential to bring new therapies to patients.
“Basic scientists cannot get to the bedside without a clinician, and the clinician cannot get to the bedside with an innovative therapy without a collaborator from the basic science department,” she says. “91九色视频 supported this collaboration on campus to ensure that the research made it to the bedside.”
Recommended
