DENVER -- Gene therapy for hemophilia B. shows highly encouraging results in early phase I clinical testing, Dr. Catherine S. Manno reported at the annual meeting of the American Society of Gene Therapy.
None of the six adult patients treated thus far has developed any evidence of local or systemic toxicity or germline transmission of the viral vector.
And although the first three received a dose of gene therapy so low that investigators anticipated no clinical effect based upon animal models, in fact, two of the three responded with a clinically meaningful rise in circulating Factor IX levels and a corresponding reduction in need for infusion of plasma concentrates in the following year, said Dr. Manno of Children's Hospital of Philadelphia.
The hemophilia B trial, funded by Avigen, involves administration of the gene coding for expression of coagulation Factor IX. The gene is contained in an adeno-associated virus (AAV) vector injected under ultrasound guidance into the quadriceps muscle. The goal is to induce the patient's skeletal muscle to produce and secrete Factor IX persistently at levels high enough to prevent bleeding episodes. It's been done successfully in mice and dogs--and now it has been done in patients.
A gene-based therapeutic approach to hemophilia would overcome several significant shortcomings of conventional plasma concentrate infusions. For one, the concentrates used are very expensive: $50,000-$10,000 per year for an adult with severe hemophilia.
Moreover, the protein-based plasma concentrates have a half-life of just 8-12 hours and are typically given episodically; most patients with severe disease have chronic joint damage because of treatment delays. HIV and hepatitis transmission via these blood products is no longer an issue, but transmission of other blood-borne diseases remains possible.
With gene therapy in its nascent stages, hemophilia B is a particularly attractive target. It offers an exceptionally wide therapeutic window. Patients whose circulating Factor IX level is 150% of normal obtain clinical benefit. At the other extreme, boosting the Factor IX level from undetectable to just 1%-5% is sufficient to transform severe disease into moderate disease, which means a much more benign clinical course, less risk of spontaneous life-threatening hemorrhages, and far lower medical costs. This is the goal of the gene therapy program, Dr. Manno explained at the meeting, also sponsored by Mount Sinai School of Medicine.
The only trial data currently analyzed are from the first three patients in the low-dose therapy arm, who received 2 x [10.sup.11] genomes per kilogram of body weight. Although animal studies suggested this should not result in measurable levels of circulating Factor IX, the first treated patient had a Factor IX level of 1.8% at 3 months postinjection. At 11 months, the level remains 0.8%, and the patient's medical records indicate 40% fewer plasma concentrate infusions than prior to gene therapy A second patient in the low-dose arm also developed measurable levels of circulating Factor IX, although they never rose above 1%.
The AAV vector is derived from a replication-defective parvovirus with a small single-stranded DNA genome. All six patients treated had preexisting AAV antibodies. Infection is not associated with any known illness.
Dosing of the gene therapy is tricky. Animal data indicate that although Factor IX levels climb with higher-dose therapy, so does the risk of developing inhibitory antibodies following an intramuscular injection. Should this occur, Avigen has indicated that it would develop a second serotype of AAV Factor IX, she said.
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