First Results in Humans for Antisense Oligonucleotide Treatment of Patients with Huntington’s Disease

Tuesday, April 24, 2018


At the American Academy of Neurology meeting in Los Angeles, researchers Sarah Tabrizi, Blair Leavitt, Holly Kordasiewicz, and others presented their results using antisense oligonucleotides (ASO) (IONIS-HTTRx; Ionis, San Diego, CA) for treatment of patients with Huntington’s disease. In a study designed to characterize safety, tolerability, pharmacokinetics, and pharmacodynamics  of ASO, these researchers found that ASO was well-tolerated at all doses tested, and that adverse events were mostly mild with no patients discontinuing treatment during the study.

Most importantly, they found that treatment with ASO significantly reduced the levels of mutant huntingtin protein (HTT), in the CSF of patients treated with ASO, in a dose-dependent manner. This is the first time that ASO has been used in humans. These results suggest that ASO has the potential to modify disease course, slowing progression of the illness, and that ASO may be useful for treatment of other diseases in which the mutant protein has been identified and sequenced. Huntington’s disease is an autosomal dominant neurodegenerative disease caused by a gain-off-function mutation.

In previous preclinical studies, in mouse models of Huntington’s disease, treatment with ASO lowered levels of HTT and also delayed disease progression and reversed disease symptoms. in this Phase 1/2a trial in early stage HD patients, ASO delivered via IT injection was well tolerated with no drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTTRx is a promising therapeutic for the treatment of HD.

"Since the discovery of the gene that causes Huntington's disease 25 years ago, we've been working to discover a drug that targets the cause of the disease—the mutant huntingtin protein. (These results) give us hope that this new drug may have the potential to slow, or perhaps halt, the progression of this devastating disease," said Dr. Sarah Tabrizi, Professor of Clinical Neurology, Director of the University College London's Huntington's Disease Centre and the global lead investigator on the study. "The next step is to advance the drug into a larger study designed to demonstrate the potential clinical benefit of reducing the toxic mutant huntingtin protein in people with Huntington's disease."

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