ARTICLE IN BRIEF
In a mouse model of Huntington's disease, investigators were able to suppress mutant huntingtin and restore cognitive function and behavioral deficits.
Researchers at the University of British Columbia have suppressed expression of mutant huntingtin (muHTT) using allele-specific antisense oligonucleotides (ASOs) in a mouse model of Huntington disease (HD), preventing and in some cases reversing deficits in cognitive function and behavioral symptoms.
They also found robust HTT suppression throughout the cortex and limbic system in nonhuman primates using ASOs analogous to human versions, according to the study, which was published online October 3 by Science Translational Medicine.
A non-allele-specific version of the ASO has already demonstrated significant HTT reduction in human subjects, and a two-part global clinical trial is set to begin in the near future.
HD is caused by CAG expansion in the HTT gene. This results in unstable, elongated proteins that are toxic to neurons. ASOs bind to messenger RNA to prevent synthesis of expression of the mutation.
The researchers and other genetics investigators have predicted that ASOs targeting and silencing three to five of these polymorphisms could help 80 percent to 90 percent of HD patients worldwide.
In 2011, these investigators first identified single nucleotide polymorphisms (SNPs) that disrupt normal expression of huntingtin, and in 2014 they reported development of ASOs that selectively suppressed A1 mutant HTT. Huntingtin plays a role in a number of functions in the body, but when mutated it is toxic, making it important to retain normal levels while targeting the mutant version.
The team used both a total HTT-suppressing ASO as well as allele-specific muHTT ASOs in a humanized rodent model of HD to determine whether HTT suppression could improve cognitive and psychiatric endpoints. They also evaluated whether the time of administration affected the results.
One of the ASOs targeting muHTT had the greatest effect with 89 percent suppression for 46 weeks or longer, without affecting wild type huntingtin. There was no effect on control mice. In addition, suppression was also seen in HD mice with significant motor deficits treated at six-months.
Cognitive deficits and psychological symptoms were prevented and reversed in some of the treated mice.
The researchers assessed cognitive performance by observing whether the mice could identify and show preference for specific objects. All three ASOs prevented development of spatial learning problems in mice treated early and restored normal spatial learning in mice treated after symptom development. Both total and allele-selective HTT suppression improved cognitive performance regardless of when treatment was initiated with the most robust ASO.
Anxiety testing in the most responsive mutant strain of mice also showed both prevention and rescue benefits and restored normal explorative behavior. The findings indicated that treatment using the more robust ASOs, or continued HTT suppression, is needed to treat such symptoms in HD mice, said Michael R. Hayden, PhD, professor of medical genetics and senior scientist at the Center for Molecular Medicine and Therapeutics, at the University of British Columbia, Vancouver.
“Because the cognitive and psychiatric symptoms in HD patients are often reported as being the most detrimental, a benefit in these areas would have high therapeutic impact,” he told Neurology Today.
Brain analysis showed that late administration with ASOs suppressing muHTT ameliorated atrophy in the forebrain and induced significant preservation in forebrain weight, however only allele-specific muHTT suppression prevented striatal cell loss.
“There is a reasonable expectation that, with a disease-modifying therapy such as gene suppression, by targeting muHTT in areas of the brain implicated in HD, it may be possible to alter many aspects of disease,” Dr. Hayden said.
In the non-human primates, the research team confirmed that ASOs likewise suppressed HTT in cortical and limbic regions, but not the basal ganglia, when delivered by bolus once each week in ascending doses for a total of 30 mg over four weeks.
“Our findings support use of ASOs as a therapeutic for HD and provide a rationale for including cognitive and psychiatric endpoints in future human trials,” Dr. Hayden said.
“HD affects the cortex and deeper layers of the brain, so a big issue is delivery to the right region. With intrathecal treatment patients would have to undergo lumbar puncture once a month, so establishing viable, improved delivery is an important goal for our lab.”
If all goes well, he said, the results of the phase 3 trial could be ready within three to five years.
Commenting on the findings, Kenneth H. Fischbeck, MD, FAAN, an NIH Distinguished Investigator in the Neurogenetics Branch of the National Institute of Neurological Disorders and Stroke, said: “ASO research has considerable translational importance, and I think this study is a step forward in the field. Nonetheless, it is important to view the findings within the context of what else is going on using these ASOs in neurological disorders.”
Earlier this year, HD researchers reported successful safety and efficacy data in a phase 1-2 clinical trial for a non-allele-specific ASO targeting muHTT, which safely reduced CSF HTT protein in early HD patients by 40 to 60 percent.
“To evaluate the effectiveness of the ASO will require a larger number of patients, followed for a longer period of time,” he said.
“Toward this end, a phase 3 global study is expected to begin early next year. It will enroll up to 660 patients with HD at 80-90 sites in approximately 15 countries and seek to determine effects of lowering huntingtin over a longer period, whether there are any unexpected safety concerns, and whether sustained treatment can slow, stop, or even reverse progression,” Dr. Fischbeck told Neurology Today.
“If it is possible to develop an effective allele-specific HD ASO, it could serve as an alternative or back-up for the non-allele-specific version,” he said, adding that other advances using ASOs against inherited neurological disorders are encouraging.
In December 2016, the US Food and Drug Administration (FDA) approved nusinersen, another ASO, as the first drug to be cleared for children and adults with spinal muscular atrophy (SMA), and on October 5 of this year, the FDA approved the ASO inotersen for treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hTTR).
“Studies with these agents have demonstrated both safety and efficacy, and I think in the upcoming global clinical trial researchers could actually see some reversal of disease manifestations in HD,” Dr. Fischbeck said.
Michelle Gray, PhD, assistant professor of neurology and neurobiology at the University of Alabama, Birmingham said the study addresses a very critical question — whether technologies to reduce mutant HTT will be beneficial in reducing the cognitive and psychiatric deficits in HD without affecting the normal activity of huntingtin.
“Overall, this study reveals ASO technology can restore cognitive and psychiatric function. They also show in a non-human primate a reduction in HTT levels in cortical and limbic structures after lumbar puncture, demonstrating that the regions implicated in cognitive and psychiatric control can be reached by this method.”
“This work has important implications,” she continued. “First, it describes the use of allele-specific ASOs with the ability to reduce muHTT selectively. This provides the ultimate personalized medicine approach while also being able to address cognitive and psychiatric control.”
However, she added that it is important to remember that while the mouse model used in the study exhibits significant brain atrophy, it does not exhibit the significant neuronal cell death observed in HD patients, and amelioration of these deficits may not be possible in patients with significant neuronal loss.
“The positive cognitive changes are highly significant given that very few interventions can reverse cognitive deficits. Additionally, one has to be aware that many of the psychiatric deficits observed in HD patients can already be treated well with current therapies. Nonetheless, this work highlights two domains of the clinical manifestation of HD that is overlooked in assessing disease modification therapies.”