Editors' ChoiceGene Therapy

Factoring in new gene therapy treatments for hemophilia A

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Science Translational Medicine  10 Jan 2018:
Vol. 10, Issue 423, eaar7511
DOI: 10.1126/scitranslmed.aar7511


Delivery of a modified factor VIII gene leads to dramatic improvement of severe hemophilia A in human trials.

Hemophilia A is an X-linked disorder characterized by spontaneous bleeding in muscles and joints as well as increased risk for intracranial hemorrhage. The disease is caused by a deficiency in the functional plasma clotting factor VIII (FVIII) resulting from mutations in the FVIII gene. Currently available treatments are limited to frequent administration of exogenous FVIII following a bleeding event, although the benefit of such treatment lasts less than a day.

In a recent study, scientists working in the UK have reported successful outcomes from a recent clinical trial for gene therapy to permanently treat severe hemophilia A. Rangarajan and co-workers used adeno-associated virus to deliver a codon optimized version of the human factor VIII gene, which was also shortened by deleting a discrete portion of the gene to better fit the coding sequence into the viral vector. The nine patients, who were all adult men with severe hemophilia and no immunity to the virus, had experienced at least 12 bleeding episodes in the year previous to the study.

Vector was administered systemically into three cohorts of patients, making up low, medium, and high dose groups. The therapy was generally well tolerated, with no severe adverse reactions likely due to the treatment. The reactions reported included a transient increase in some patients in the enzyme alanine aminotransferase (indicative of liver toxicity), which was treated and resolved with prednisolone. Expression levels of FVIII were dose-dependent, with the high dose group reaching sustained therapeutic levels near to normal for a year after treatment. Bleeding events dropped from a median 16 events per year before treatment to 1 after gene therapy treatment, allowing for a complete cessation of prophylactic FVIII treatments. Only one patient from the high-dose group used on-demand factor VIII therapy for self-diagnosed bleeding after gene therapy, on one occasion seven weeks after the treatment. These significant positive results may indicate that a cure for severe hemophilia A is within reach and further support the promise of gene therapy approaches for inherited disease.

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