Single Treatment with Antisense Drug Provides Long-Term Relief from Huntington’s Disease Symptoms

A single treatment with a drug designed to block production of toxic, mutated huntingtin protein was shown to reverse progress of the disease, prevent loss of brain function, and promote survival in rodent and non-human primate Huntington’s disease (HD) models.

Investigators at the University of California, San Diego (USA) created a drug comprised of “antisense” oligonucleotides (ASOs) that catalyzed RNase-mediated degradation of huntingtin mRNA, which blocked production of mutant huntingtin while not effecting production of the normal form of the protein.

The drug was used to treat both mouse and non-human primate models of severe HD. Results published in the June 21, 2012 issue of the journal Neuron revealed that a single injection of the ASO into the cerebrospinal fluid of the experimental animals not only delayed disease progression but mediated a sustained reversal of disease symptoms that persisted longer than the transient blocking of huntingtin mRNA production. The drug produced rapid results with treated mice moving better within one month and achieving normal motor function within two. ASO infusion into nonhuman primates effectively lowered huntingtin in many brain regions targeted by HD pathology. Effects of the drug persisted for more than nine months after its administration.

“For diseases like Huntington's, where a mutant protein product is tolerated for decades prior to disease onset, these findings open up the provocative possibility that transient treatment can lead to a prolonged benefit to patients,” said senior author Dr. Don W. Cleveland, professor of cellular and molecular medicine at the University of Calilfornia, San Diego. “This finding raises the prospect of a “huntingtin holiday,” which may allow for clearance of disease-causing species that might take weeks or months to re-form. If so, then a single application of a drug to reduce expression of a target gene could “reset the disease clock,” providing a benefit long after huntingtin suppression has ended.”

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