A new gene therapy clinical trial presents a potential cure for hemophilia B, a disease that prevents proper blood clotting – with only a single doctor’s visit. The results of the international clinical trial, which included a Canadian branch headed by Dr. Jerry Teitel at St. Michael’s Hospital, were published last week in The New England Journal of Medicine.
Hemophilia B is caused by a mutation in the factor IX gene, which reduces the amount of factor IX protein produced, sometimes eliminating it entirely. Factor IX is one of several proteins needed to cause blood clotting. With reduced factor IX protein levels, the mildest trauma can cause life-threatening hemorrhaging.
While today hemophilia B is largely treatable, the current treatment leaves much to be desired. Patients require regular visits to the doctor for costly infusions of factor IX to prevent or control bleeding. Additionally, some patients require frequent blood transfusions, which more than one study has found might be shortening the average lifespan of those with hemophilia B by increasing their risk of accidental exposure to blood borne infections.
Instead of treating the disease by supplying the factor IX protein, this new clinical trial eliminates the disease by supplying a functional factor IX gene.
The clinical trial recruited 10 patients with hemophilia B. The entire treatment, just a single infusion of an inactive virus containing a more potent naturally occurring variant of the factor IX gene, lasted only an hour. A week after infusion, the newly introduced factor IX was able to cause clotting in the trial patients, and stable expression of the new gene was achieved after 14 weeks.
The clinical impact of the new gene was profound. The number of annualized bleeding events, such as significant bruising or nosebleeds, which often happen spontaneously in hemophilia B patients, was significantly reduced from an average of about 11 events in the year before the gene therapy, down to an average of fewer than one event in the year following the gene therapy. Nine of the 10 patients, in fact, didn’t experience a single bleeding event in the year following treatment.
The patients became relatively free from their regular factor IX infusions as well. In the year before the gene therapy, the ten patients had, on average, 67.5 infusions of factor IX. In the follow-up period following the gene therapy, eight of the patients hadn’t had a single factor IX infusion, while the remaining two patients had between 85%-98% reduction in number of infusions.
Given the high cost of factor IX infusions, the scientists leading the trial estimate a cost savings of $3.6 million over the course of the follow-up period alone.
While the results of the trial are remarkable, the long-term safety of the viral gene therapy hasn’t been assessed. A particular concern surrounding any proposed gene therapy is the risk of insertional mutagenesis – the new gene being inserted into the genome somewhere it shouldn’t be. In a previous gene therapy clinical trial for X-linked severe combined immune deficiency, or X-SCID, for example, a few of the children treated eventually developed leukemia as a result of their treatment. The scientists behind the new clinical trial, however, are wading cautiously.
First, they delivered the gene on a vector that tends to remain separate from the genome, avoiding insertion entirely. Additionally, the gene-delivery vector tends to infect specific types of cells – in this case the cells of the liver, where factor IX is naturally produced. By selectively targeting the cells of the liver, which don’t divide as often as other cell types, the risk of insertional mutagenesis is reduced even further. Lastly, the scientists strategically used a gene variant that’s naturally over-active, allowing them to use a dose that’s up to 120 times lower than those in other ongoing gene therapy trials.
The authors of the study hope to follow up the success of this clinical trial with a second clinical trial using a larger sample of patients, and hope to more thoroughly define the long-term safety of the gene therapy treatment.
For now, it looks like correcting the underlying cause of the disease, the genetic mutation, might be possible – and all it might take is an hour-long IV infusion.