Gene Transfer Restores Clotting Factor Level in Hemophilia B

Ricki Lewis, PhD

December 13, 2011

December 13, 2011 — Transfer of the factor IX gene into hepatocytes via peripheral vein infusion is effective against hemophilia B, report Amit C. Nathwani, MD, PhD, from University College London, United Kingdom, and colleagues in an article published online December 10 in the New England Journal of Medicine.

Hemophilia B (Christmas disease) is an X-linked recessive disorder caused by a deficiency of factor IX coagulation factor (FIX). Since the late 1960s, treatment has been intravenous injection of FIX 2 to 3 times a week. The treatment is not curative, is very costly, and can lead to production of inhibitors. Introducing a functional gene into hepatocytes and raising FIX levels just slightly above 1% of normal could restore clotting ability.

Previous experiments using adeno-associated virus serotype 2 (AAV2) to deliver the FIX gene had transient effects as a result of T-cell response against the capsid. The new phase 1/2 clinical trial used AAV8, which has a natural affinity for the liver, making peripheral delivery safer. The researchers also improved the likelihood of success with a liver-specific promoter that helped target the vector, and with use of a codon-optimized factor IX construct that increases transgene expression.

The investigators used a dose-escalation protocol in the trial, delivering a single low, intermediate, or high dose of the vector into the peripheral veins of 6 men with severe hemophilia B. The team measured the patients' FIX levels for 6 to 16 months after gene transfer. (AAV8 vectors are expressed in the livers of large animals for up to 10 years.)

In all participants, FIX levels increased to between 2% and 11% of normal in a roughly dose-dependent manner. The improved FIX production after gene therapy enabled 4 patients to discontinue receiving prophylactic FIX without spontaneous hemorrhaging, and the other 2 patients could go longer between injections.

All participants showed humoral immune response against the capsid, but none produced antibodies against the transgene. However, patients treated at the intermediate and high doses manifested a T-cell response against the capsid, although it was limited to peripheral blood and resolved with short-term glucocorticoid therapy. One man had a transient, asymptomatic elevation of serum aminotransferase level, and another had slightly increased liver enzyme levels that may have been a response to intense exertion.

The researchers cite the need for investigation of the immune response to the vector in a larger patient group. "[T]his 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," they conclude.

The sustained treatment of hemophilia B with gene transfer is a "landmark study," writes Katherine Ponder, MD, from Departments of Internal Medicine and Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, in an accompanying editorial, because it is the first to demonstrate long-term expression of a blood protein associated with clinical improvement. The lifetime cost of intravenous factor IX can exceed $20 million per patient, making the existing treatment unfeasible in developing nations, Dr. Ponder points out. The cost of the vector per patient is $30,000. She adds that a possible adverse effect could be fulminant hepatitis if a patient has recently had an AAV8 infection.

Three article coauthors have patents pending and/or licensing arrangements with Amsterdam Molecular Therapeutics for parts of the gene transfer construct. One coauthor consults for bluebirdbio, Inc; Forrest Research Labs; Shire Inc; Tacere Therapeutics; and Roche, and has received payments for lectures from Novo-Nordisk, Biogen-Idec, and Baxter Healthcare. Katherine Ponder reports receiving payments for lectures or speakers bureau activities for Shire and Genzyme.

N Engl J Med. Published online December 10, 2011. Full text, Editorial

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