Nature Medicine | Spoonful of Medicine

A whole clot of hope for new hemophilia therapies

People with hemophilia have a lot of reasons to be hopeful these days. A December gene therapy study showed early success, and yesterday the Dublin-based pharmaceutical company Shire announced a partnership with the Richmond, California-based biotech Sangamo BioSciences. Together, the companies plan to develop hemophilia treatments that target defects in four clotting factor genes with the zinc finger DNA-binding protein technology developed by Sangamo. Shire will provide financial support to bring these therapies through clinical testing.

Sangamo’s gene-editing technology, which enables the alteration of any DNA sequence in any gene, first made hemophilia news last June. A team of researchers from the Children’s Hospital of Philadelphia (CHOP) showed that the technology could correct the genetic defect that causes hemophilia B in a mouse model of the disease without poisoning the liver, a perennial concern with treatments like these that are injected directly into the organ.

Current treatment for hemophilia involves adding clotting factors to a patient’s blood. A gene-editing therapy, such as the one Shire and Sangamo plan to pursue, would target the disease at its source in the genome rather than just alleviating symptoms.

Sangamo is not alone in pursuing gene therapy treatments for hemophilia. A host of researchers have made strides toward developing therapies using adenovirus-associated viral (AAV) gene delivery systems that target dysfunctional clotting factor IX in hemophilia B, one of the four factors Sangamo plans to target as well. A phase 1 trial published in December in the New England Journal of Medicine showed that an AAV treatment for hemophilia B improved clotting. A second phase 1 trial at CHOP is testing a slightly different AAV treatment that also targets factor IX. Katherine High, a hematologist at the University of Pennsylvania in Philadelphia, says she expects to see more trials being launched in the next couple years.

Although AAV factor IX therapy is farther along in development than the zinc finger nuclease technology, High says Sangamo’s approach should not be discounted. Because zinc finger nuclease therapy introduces a correction into the genome, which likely means the correction will be passed to daughter cells, this treatment may “have the advantage of being very long lasting,” High says. Whether AAV therapies could achieve such long-term results is not yet known. The immune system may clear clotting factors produced by the virus, causing the therapy to lose potency over time.

Photo courtesy of Bruce Wetzel via Wiki Creative Commons

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