Perspective: The fix is in | Nature

History explains why people with haemophilia, and their physicians, are cautious to believe that a cure is in sight, says Stephen Pemberton. Credit: Heather van Uxem Lewis In 2011, a

remarkable study1 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 virus2. > Researchers are hesitant about gene therapy owing to the unresolved > ethical issues. 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 doctors3. 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 disease4. 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. The memory of tainted transfusions still haunts those who have, or work with, haemophilia. Add Gelsinger's death into the mix and it is clear why specialists are

debating thorny ethical problems, such as when to try out AAV-mediated gene transfer on children. Gene therapy is not even the most promising treatment for haemophilia on the immediate

horizon. The biotechnology industry is producing recombinant-clotting-factor products for both haemophilia A and B that can limit bleeding episodes with less-frequent injections (see page

S162). But the lure of a less-intrusive form of treatment raises a historical spectre of its own. It was this same desire for convenience that led many haemophilia physicians and patients in

the United States in the 1980s to continue using clotting-factor concentrates that had a high risk of HIV contamination rather than switch back to older, more cumbersome but less risky

forms of plasma-replacement therapy. Thousands of people with haemophilia contracted HIV and HCV because of this acculturated preference4. Finally, there is the difficulty of making costly

treatments available to the vast majority of the world's haemophilia patients who live in low income countries. About 75% of people with haemophilia still receive inadequate treatment,

particularly in less-developed nations where clotting-factor therapy is limited5. An effective gene therapy could well offer these underserved patients their first chance at effective

intervention6. History suggests that the fix will not lie in just one solution, but will be contextual and messy. The wants and needs of people with haemophilia in the developed world might

not be the same as for those in low income countries. Yet social justice demands that there be equity in access to treatment. The transfusion scandals of the past remind us of the importance

of bringing together patients and treatment professionals with stakeholders from industry and public health to weigh the various technological fixes. If such discussions had taken place in

the 1970s and 1980s about the known problem of transfusion-related hepatitis B, the haemophilia community would not have been blind-sided by the emergence of HIV and HCV. REFERENCES *

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(2014). Article  CAS  Google Scholar  * Wailoo, K. & Pemberton, S. _The Troubled Dream of Genetic Medicine: Ethnicity and Innovation in Tay-Sachs, Cystic Fibrosis, and Sickle Cell

Disease_ (Johns Hopkins Univ. Press, 2006). Google Scholar  * Pemberton, S. _The Bleeding Disease: Hemophilia and the Unintended Consequences of Medical Progress_ (Johns Hopkins Univ. Press,

2011). Google Scholar  * Mannucci, P. M. _Haemophilia_ 17 (Suppl. 3), 1–24 (2011). PubMed  Google Scholar  * High, K. A. & Skinner, M. W. _Mol. Ther._ 19, 1749–1750 (2011). Article  CAS

  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Stephen Pemberton is a medical historian at the New Jersey Institute of Technology in Newark, and author

of The Bleeding Disease: Hemophilia and the Unintended Consequences of Medical Progress., Stephen Pemberton Authors * Stephen Pemberton View author publications You can also search for this

author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Stephen Pemberton. RELATED LINKS RELATED LINKS RELATED LINKS IN NATURE RESEARCH The history of hemophilia Gene Therapy

for Hemophilia: Addressing the Coming Challenges of Affordability and Accessibility Hemophilia Gene Therapy: A Holy Grail Found Mortality before and after HIV infection in the complete UK

population of haemophiliacs https://doi.org/10.1038/mthe.2002.0703 Blog post: A whole clot of hope for new hemophilia therapies Blog post: Gene therapy success for haemophilia RELATED

EXTERNAL LINKS Review of 2011 NEJM Study National Hemophilia Foundation report on gene therapy research RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Pemberton, S. Perspective: The fix is in. _Nature_ 515, S165 (2014). https://doi.org/10.1038/515S165a Download citation * Published: 26 November 2014 * Issue Date: 27 November 2014 * DOI:

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