Editors' ChoiceHEMOPHILIA

Personalizing the royal treatment for hemophilia

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Science Translational Medicine  20 Apr 2016:
Vol. 8, Issue 335, pp. 335ec64
DOI: 10.1126/scitranslmed.aaf6935

Hemophilia, perhaps more than any other monogenic disease of childhood, has been mythologized in popular culture. Its moniker is “the royal disease” because Queen Victoria’s descendants were affected, it contributed to the Russian Revolution a century ago, and it regained media attention in the 1980s when children acquired AIDS from pooled human Factor VIII (FVIII) products. Despite popular awareness of the disease, treatment of severe FVIII deficiency remains challenging. In response to the AIDS crisis, recombinant FVIII products were developed to avoid human plasma exposure and have become the most common treatment. Yet a recent randomized trial found that children receiving recombinant FVIII were 70% more likely to develop neutralizing FVIII antibodies, called inhibitors, than those receiving plasma-derived FVIII concentrates. These inhibitors block the blood-clotting properties of FVIII. Alternative treatments for severe hemophilia are less effective at preventing bleeding than FVIII replacement, so patients with inhibitors require immune tolerance therapy. This process aims to eliminate the immune response to FVIII but is expensive, cumbersome, and frequently unsuccessful.

Against this backdrop, Gorski and colleagues undertook whole-exome sequencing to search for genetic variants associated with inhibitor formation in a cohort of Italian boys with severe FVIII deficiency. Some of their candidate mutations were related to immune function, but the most strongly associated change in the discovery and validation cohorts was a missense mutation in the lactase gene (LCT). What role could lactase, the enzyme that digests lactose, play in preventing inhibitor development? The authors speculate that the protective effect may be due to another gene linked to the LCT mutation in a highly conserved haplotype, rather than lactase itself.

Whole-exome studies require confirmation in independent cohorts, so this finding is not definitive. However, the possibility of personalized medicine for severe hemophilia may be on the horizon. If hematologists could accurately predict inhibitor risk from genetic profiling, perhaps FVIII replacement therapy could be tailored to maximize protection from bleeding while minimizing inhibitor development. Hopefully, future clinical trials in hemophilia will incorporate genetic risk prediction to individualize FVIII treatment.

M. M. Gorski et al., Whole-exome sequencing to identify genetic risk variants underlying inhibitor development in severe hemophilia A patients. Blood 10.1182/blood-2015-12-685735 (2016). [Abstract]

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