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History explains why people with the malady, and their physicians, are cautious to believe that a cure is in sight

HEATHER VAN UXEM LEWIS

In 2011, a remarkable study in the New England Journal of Medicine detailed the successful treatment of six adults with haemophilia B, which is caused by a deficiency in the coagulation protein known as factor IX. All of the participants were able to eliminate or reduce the frequency of clotting-factor-replacement injections the current standard treatment for the disease after their livers began producing functional levels of factor IX. The experimental therapy came in the form of an adeno-associated virus (AAV) carrying a gene that encodes instructions for production of normal levels of human factor IX. Three trials of AAV-mediated gene transfer in patients with haemophilia B are ongoing, with high expectations.

After more than 20 years of research on gene transfer, it is a promising time for haemophilia therapies. It now seems likely that a single-dose treatment for haemophilia B using an AAV or another gene-transfer technique will be a viable option for many people in the next decade or two.

Yet haemophilia researchers are not inclined to speak enthusiastically of a cure. Part of that caution comes from recognition that there are still problems to solve. For example, some 40% of people with haemophilia B would find no refuge in an AAV treatment because they produce antibodies that attack and neutralize this virus.

And even if that problem were solved, the treatment would apply only to those with haemophilia B. The more common form of the condition, haemophilia A, stems from a deficit in another protein factor VIII and the gene for that protein is a more difficult target. Regardless of the type of haemophilia, researchers remain hesitant about gene therapy owing to the unresolved ethical issues that arose decades ago.

The unfettered optimism that characterized the early years of gene-therapy research came to a screeching halt in 1999, when 18-year-old Jesse Gelsinger died in a phase I clinical trial at the University of Pennsylvania in Philadelphia. Gelsinger had undergone an experimental gene transfer for his otherwise treatable metabolic disorder. His death, along with a series of other harmful events in early gene-therapy trials for a variety of diseases, threatened the whole field.

Haemophilia specialists who were engaged in gene-transfer studies were more guarded than most of that era's self-proclaimed gene doctors. The source of their reserve goes beyond the cautious optimism that characterized such research after 1999; it is grounded instead in the long and troubled experience that the haemophilia community has had with technological fixes.

By the late 1970s, a therapeutic revolution had transformed haemophilia from an obscure hereditary malady into a manageable disease. But the glory of this achievement was tragically short-lived. The same clotting-factor-replacement therapies that delivered a degree of normality to the lives of people with haemophilia brought unexpected and fatal results: tens of thousands of people with haemophilia were diagnosed with transfusion-related HIV/AIDS in the 1980s and with hepatitis C virus (HCV) in the 1990s.

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Gene Therapys Hemophilia Promise Is Tempered by Memories of Past Tragedies