Description
NHLBI research and tech transfer teams develop therapy for private sector
For people with the bleeding disorder known as hemophilia B, frequent and excessive bleeding can limit physical activity and deeply affect their quality of life. But a new treatment strategy – while not a cure – is giving patients hope for long-term control over this inherited disease.
Hemophilia B is caused by the lack of an important blood clotting protein called coagulation factor IX (FIX). To be treated, most patients receive a standard replacement therapy, which delivers the FIX protein to them intravenously. This can be done as needed for mild and moderate cases or on an ongoing preventive basis for severe cases. These treatments not only are invasive, but they can have side effects, such as allergic reactions and infections. Also, many patients develop antibodies to FIX that limit its effectiveness.
One gene therapy approach, however, is showing promise as a more durable treatment with fewer side effects. It builds on pioneering advances in the gene therapy field and is based on technology first developed at NHLBI. The method uses a unique viral shell, or vector, to provide patients’ cells with a working copy of the FIX gene. This allows the patients’ own cells to produce FIX, potentially eliminating the need for replacement therapy altogether.
In June 2021, uniQure, a biotech company based in Amsterdam, announced results from an ongoing phase 3 clinical trial of this gene therapy. They showed that even one year after a single gene therapy injection, study participants produced stable levels of FIX, had fewer bleeding episodes, and most were able to stop their replacement therapy. In December 2021, the company announced another milestone with positive results, and it plans to seek regulatory approval in 2022.
The technology is rooted in basic research on viruses. “We were interested in virology, not vectorology,” said Robert Kotin, Ph.D., who characterized and patented the vector used in uniQure’s study. In the 1990s, Kotin worked as an investigator in the NHLBI Division of Intramural Research. He is now a professor at the University of Massachusetts Chan Medical School and also scientific co-founder of Generation Bio and Frontera Therapeutics.
In the 1990s, Kotin and his lab colleagues at NHLBI were interested in how different viruses interact with host cells. They found that one of the viruses they were studying had a very distinct outer shell, known as the capsid. Subsequent work by John Chiorini, Ph.D., then a post-doctoral fellow in Kotin’s lab, and others in the field, showed that the new capsids could interact with a wide range of cells, and that the combination of vector genome and capsid is critical for successful gene delivery.
To turn these discoveries into a useful therapy, Kotin worked closely with NHLBI’s Office of Technology Transfer and Development (OTTAD)[1]. OTTAD helped file patents for the newly discovered viral capsids, an important step in making a potential new therapy available for development and testing across public and private sectors.
Still, barriers emerged. A major challenge was figuring out how to produce enough viral vector to deliver therapeutic levels of FIX (and other genes) to patients. At a scientific meeting in the early 2000s on gene therapy for Duchenne muscular dystrophy, Kotin recalled hearing about another researcher’s positive results for viral vector approaches in animal models of the disease. But, when a parent at the meeting asked the presenter how soon children could be enrolled in a trial, the speaker responded that there was currently no way to produce enough virus to continue pre-clinical trials, much less begin testing on patients.
Kotin was inspired to get his lab working on the problem. “We were a small group, maybe six people,” he said. “It was difficult to compete with larger groups sometimes, but we were very competitive in innovation.” His group realized that the vectors they were studying were similar to some viruses known to infect insects. By growing the vector in insect cells, the team was able to scale up vector production and make it cleaner and more efficient. Kotin again sought OTTAD’s help in bringing the new technology to the private sector. Since then, he noted, the method has become a staple in modern virology research and is one of the primary ways used to manufacture viral vectors.
Kotin believes that his research could not have been done without the ability to pursue basic research as part the NHLBI intramural program. When he was hired by then NHLBI Scientific Director Dr. Ed Korn, he remembers being told, “we have the opportunity, if not the obligation, to do research that could not be done elsewhere.”
The discoveries Kotin made while working at the NHLBI have helped pave the way for a new generation of therapeutic technologies. Today, Kotin’s capsid discoveries and vector production methods are used in labs around the world. Thanks to these advances, numerous clinical trials of viral vector gene therapies are underway for a wide range of diseases, giving hope to patients and families everywhere.
[1] NHLBI’s technology transfer specialists help our clients navigate the technology development pathway from discovery to commercialization and connect our partners to world-class scientists and cutting-edge technologies. Contact our OTTAD team today for your personalized development plan.