What is the role of gene therapy in the treatment of factor IX deficiency (FIX) (hemophilia B)?

Updated: Mar 09, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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Several approaches to gene therapy have been undertaken in treating patients with severe hemophilia B. Considerable success has been reported with systemic administration of an adeno-associated virus (AAV) encoding an optimized factor IX construct, although efforts to maintain long-term FIX expression continue. [29] Basal levels of 5-10% significantly ameliorate bleeding in persons with severe hemophilia.

Nathwani et al reported long-term efficacy and safety of gene therapy in 10 patients with severe hemophilia B using an AAV serotype 8 (AAV8) vector, scAAV2/8-LP1-hFIXco, that contains a codon-optimized modified FIX transgene. After a single intravenous infusion of the vector, circulating FIX levels increased to 1% to 6% of normal in all 10 patients over a median of 3.2 years. Four of the seven patients previously on factor replacement were able to discontinue it, and the others were able to decrease the dose. [30]

The most significant toxicity was mild elevation of the alanine amino-transferase level that occurred 7 to 10 weeks after infusion. The increase resolved over a median of 5 days with prednisolone treatment. This contrasts with results of earlier studies that used intrahepatic administration of AAV2 vector, which did not result in long-term expression of FIX and was associated with appreciable hepatic toxicity. [30]

Nevertheless, FIX levels achieved with gene therapy, although above the current usual target trough levels achieved with FIX prophylaxis, fall well short of the level that longer-acting FIX preparations can produce. In addition, the high peak levels provided by FIX infusions permit patients to maintain an active lifestyle.

Widespread adoption of gene therapy also faces the barriers of high cost and a high seroprevalence of antibodies to AAV vectors in the general population. Other new technologies that do not require viral vectors (eg, stem cell therapy) may obviate that difficulty.

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