A new gene-silencing strategy can reverse core symptoms associated with Huntington's disease, according to a preclinical study published by Cell Press in the June 21st issue of the journal Neuron. The short-term therapy produced sustained benefits in both mouse and primate animal models of this neurodegenerative disorder, which currently lacks an effective treatment.
"Our approach is feasible for development now into a therapy for Huntington's disease in man," says senior study author Don Cleveland of the University of California at San Diego.
Huntington's disease is a fatal condition marked by uncontrolled movements and cognitive and psychiatric problems. It arises from mutations in the huntingtin gene, which cause toxic protein fragments to build up in the brain. Previous preclinical efforts aimed at blocking the production of mutant huntingtin protein have fallen short because they have been directed at a small portion of the brain. "Because huntingtin is widely expressed, targeting multiple brain regions will likely be required for an effective treatment," Cleveland says.
In the new study, Cleveland and his team reduced mutant huntingtin levels across brain regions in several mouse models of Huntington's disease and in nonhuman primates. They achieved a long-lasting drop in huntingtin levels through the transient, one-time infusion of single strands of DNA—called antisense oligonucleotides (ASOs)—which selectively bind to and degrade molecules that contain instructions for making the mutant protein.
The motor performance of treated animals started improving within 1 month and reached normal levels within 2 months. Psychiatric and motor benefits lasted 9 months after treatment, long after mutant huntingtin levels began to rise again. "This finding has implications more broadly for therapy in any of the age-dependent neurodegenerative diseases that develop from prolonged exposure to a mutant protein," Cleveland says.
Moreover, the therapy blocked brain atrophy and increased lifespan in mutant mice with a severe form of the disorder. Because ASOs have proven to be safe in clinical trials, with one approved drug and dozens under development, this approach is promising not only for Huntington's disease, but also for other neurodegenerative disorders with a known genetic cause.
Kordasiewicz et al.: "Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis."