Gene therapy achieves early success against hereditary bleeding disorder

Hemophilia is a rare blood-clotting disease famously known for afflicting the royal families throughout Europe. One type, Hemophilia B, also called Christmas disease after Stephen Christmas, the first patient described with it, is caused by a defect in the eponymous gene on the X chromosome that leads to less than 1 percent of normal expression of Factor IX (FIX), an important blood clotting factor. Hence patients, who are usually male because they only have one X chromosome, require regular intravenous transfusions of Factor IX to prevent internal bleeding, or hemorrhage. These injections cost an individual patient about $300,000 a year, which may add up to around $20 million over a lifetime.

That may soon change due to a “landmark” study published this weekend in the New England Journal of Medicine. An international research team led by scientists at the University College London successfully used gene therapy (adeno-associated viral vectors) to replace the defective or missing copy of the FIX gene in a small cohort of patients, prompting the New York Times to write that Hemophilia B may be “the first well-known disease to appear treatable by gene therapy, a technique with a 20-year record of almost unbroken failure.” The viral vector used by the team inserted the replacement gene into the liver cells of the hemophiliac patients, carefully avoiding the chromosomes to reduce the risk of inducing cancerous mutations, and induced physiologically relevant expression of the coagulation factor up to 22 months post-therapy. As the authors summarize in NEJM:hemophilia-B-gene-therapy

The development and widespread use of clotting factor concentrates for the treatment of hemophilia in the early 1970s dramatically improved the life expectancy for patients with the disease. Subsequent development of recombinant clotting factor concentrates has improved their safety profile, but there remains a strong interest in treatment strategies that would eliminate the need for long-term intravenous infusions and that would be available to the hemophilia population throughout the world. This study documents a critical step toward that goal and shows that sustained therapeutic expression of a transferred factor IX gene can be achieved in humans. The increase in FIX levels in our study participants was roughly dose-dependent, with the high dose of the vector scAAV2/8-LP1-hFIX (2×1012 vg per kilogram) mediating peak expression at 8 to 12% of normal levels. After peripheral-vein administration of scAAV2/8-LP1-hFIXco, four of the six participants were able to stop using prophylaxis with FIX concentrate without having spontaneous hemorrhage, even when they undertook activities that had provoked bleeding in the past. For the other two participants, the interval between prophylactic FIX concentrate injections was extended, but prophylaxis was not completely discontinued…

In summary, we have found that a single peripheral-vein infusion of our scAAV2/8-LP1-hFIXco vector consistently leads to long-term expression of the FIX transgene at therapeutic levels, without acute or long-lasting toxicity in patients with severe hemophilia B. Immune-mediated, AAV-capsid–induced elevations in aminotransferase levels remain a concern, but our data suggest that this process may be controlled by a short course of glucocorticoids, without loss of transgene expression. Follow-up of larger numbers of patients for longer periods of time is necessary to fully define the benefits and risks and to optimize dosing. However, this gene-therapy approach, even with the associated risk of transient hepatic dysfunction, has the potential to convert the severe bleeding phenotype into a mild form of the disease or to reverse it entirely.

Study of gene therapy developed at UCL and St. Jude Children’s Research Hospital offers first proof adults with haemophilia B benefit from treatment, reducing need for injections with clotting factor to prevent bleeds.

Symptoms improved significantly in adults with the bleeding disorder haemophilia B following a single treatment with gene therapy developed by researchers at St. Jude Children’s Research Hospital in Memphis, US and demonstrated to be safe in a clinical trial conducted by UCL.

The findings of the six-person study mark the first proof that gene therapy can reduce disabling, painful bleeding episodes in patients with the inherited blood disorder. Results of the Phase I study appear online ahead of print today in the New England Journal of Medicine. The research is also scheduled to be presented on 11 December at the 53rd annual meeting of the American Society of Hematology in San Diego, US.

Four study participants stopped receiving protein injections to prevent bleeding episodes after undergoing the therapy and have not suffered spontaneous bleeding. Several have also participated in marathons and other activities that would have been difficult prior to gene therapy. The study participants were all treated at the Royal Free Hospital in London under the care of Professor Edward Tuddenham, a pioneer in the field of blood coagulation and a study co-author.

“The first patient has been followed for the longest time, and his levels have remained at 2% for more than 18 months. These results are highly encouraging and support continued research. More patients are scheduled to be enrolled in future trials scheduled to begin later this year,” Davidoff said.

One of the participants who received the highest dose of the vector underwent successful, short-term steroid treatment after his liver enzymes rose slightly after the vector infusion. The rise signalled mild liver damage. The volunteer remained otherwise healthy, his Factor IX levels remain above pre-infusion levels and his liver enzymes have returned to normal. Liver enzymes also rose slightly, but remained in the normal range, for the other participant who received the highest dose of the vector. The participant also received a short course of steroids.

Researchers believe an immune response targeting the vector triggered the elevated enzyme levels. A similar response was reported in earlier gene therapy trials conducted by other investigators using a different vector.

The vector used in this study was produced at the Good Manufacturing Practices (GMP) facility on the St. Jude campus. The GMP operates under government-approved manufacturing guidelines and produces highly specialized medicines, vaccines and other products that pharmaceutical companies are reluctant to pursue. The vector can also now be produced in a similar facility at UCL.

The research was funded in part by The Katharine Dormandy Trust, Medical Research Council, Wellcome Trust, NHS Blood and Transplant and the UCLH/UCL National Institute for Health Research Biomedical Research Centre, all in the UK. In the US, the research was funded by the National Institutes of Health, the Assisi Foundation of Memphis and ALSAC.


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