Finally, Therapies Targeting Huntingtin Poised for Clinic

Twenty years after the identification of the mutant gene that causes Huntington’s disease, scientists are ready to take therapies that target it into human trials. Studies in mouse models suggest that transiently squelching production of the gene product, huntingtin, with antisense oligonucleotides improves motor skills and behavior for months, raising hopes that this approach might work in people (see June 2012 news ). Recently, Isis Pharmaceuticals, Carlsbad, California, announced that it will partner with Roche, headquartered in Basel, Switzerland, to further develop HD antisense technology (see press release). At least three other companies expect similar strategies for lowering mutant huntingtin to enter clinical trials in the next two or three years.

The nonprofit foundation Cure Huntington’s Disease Initiative (CHDI) provided research support to all four companies. Cristina Sampaio, chief clinical officer at the foundation, told Alzforum that because mutant huntingtin causes the disease, suppressing the protein represents one of the most promising treatment strategies. “The rationale could not be more compelling. This is where we have most of our hopes,” she said. Other potential HD therapies, such as the antihistamine Dimebon®, have failed in trials (see HORIZON Investigators of the Huntington Study Group and European Huntington’s Disease Network, 2013).

Roche will pay Isis up to $392 million to license the HD antisense technology, and will also pay royalties on any drugs that come out of the program. Roche will work with Isis to improve delivery of the oligonucleotides into the brain. Because these are large molecules, they struggle to cross the blood-brain barrier. To enhance penetrance, Roche will make use of its “brain shuttle” program (see ). Roche declined to provide details about the shuttle program to Alzforum.

Other companies are pursuing a range of methods to silence the gene. Sangamo Biosciences in Richmond, California, in collaboration with Shire AG, based in Dublin, Ireland, is developing a zinc finger DNA-binding protein to turn down expression of the mutant huntingtin gene while leaving the healthy gene untouched (see press release). Medtronic Inc., headquartered in Minneapolis, Minnesota, and Alnylam Pharmaceuticals, Cambridge, Massachusetts, will use a pump to deliver interfering RNA (RNAi) to the central nervous system (see press release). By contrast, Genzyme, also in Cambridge, is using a viral vector to deliver RNAi to neurons, Sampaio said, but that company, too, declined to provide information.

These programs still face many challenges, Sampaio said, including delivering the therapeutics to the right place and in the right quantities to halt the disease. Sampaio also noted the need for better biomarkers to measure drug effectiveness. Several ongoing studies, such as TRACK-HDTrack-On HD, and PREDICT-HD, are gathering data on imaging and behavioral changes that mark disease progression (see Tabrizi et al., 2013). Sampaio expects upcoming clinical trials to help answer many of these questions. “I’m very cautious about the first trials. I think we have a huge opportunity to learn in the next two years, but we will not have an immediate treatment, because we have to fine-tune issues about how to deliver, how to dose, and how to truly manage this technology,” Sampaio said.

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