Antisense Therapy Reverses Symptoms in Huntington Model, with Long-Term Beneﬁ Ts Investigators Envision Clinical Trial Within Two Years

10 | NEUROLOGY TODAY | AUGUST 2, 2012

Antisense Therapy Reverses Symptoms in Huntington Model, with Long-term Beneﬁ ts Investigators Envision Clinical Trial Within Two Years

BY RICHARD ROBINSON

ARTICLE IN BRIEF In contrast, in a June 21 paper in “mitigates the risk of lowering the nor- Neuron, investigators reported that the mal protein because we don’t have to Investigators reported that antisense oligonucleotide (“oligo”), a suppress it continuously to have a long- intrathecal delivery of an modifi ed form of DNA that caused the term benefi t.” antisense oligonucleotide destruction of the messenger RNA for The researchers also infused the oligo suppressed mutant huntingtin in both mutant and normal huntingtin, was into the CSF of Rhesus monkeys for a Huntington’s mouse model, injected directly into the CSF. Because 21 days, using technology similar to and the benefi ts lasted months there are no known cellular receptors that used in a recent clinical trial of anti- after the treatment was stopped. for such molecules, they are much more sense oligonucleotides for amyotrophic widely circulated before being taken lateral sclerosis. They found that the ntisense oligonucleotide treat- into cells, said the study’s senior inves- oligo distributed widely, accumulating ment in a mouse model of tigator Don Cleveland, PhD, professor in both cortex and the caudate nucleus AHuntington’s disease (HD) leads of medicine, neurosciences, and cellular of the striatum, and reduced levels of DR. HOLLY KORDASIEWICZ, to widespread suppression of mutant and molecular medicine at the Ludwig who once worked in the lab of huntingtin mRNA by 25 percent to 63 protein synthesis in the mouse brain, Institute for Cancer Research at the Uni- Dr. Don Cleveland, led the study. percent, depending on the brain region. and continues to provide benefi t for versity of California, San Diego. Holly These levels remained reduced for four months after treatment has stopped. The Kordasiewicz, PhD, who was formerly weeks after stopping treatment, and results have researchers looking forward in Dr. Cleveland’s lab and is now at Isis investigators treated 6-month old HD returned to normal after an additional to a trial in humans within two years, Pharmaceuticals in Carlsbad, CA, led mice for two weeks, and then followed four weeks. and rethinking how the mutant protein the study. them. Treatment partially reversed the Based on these results, Dr. Cleveland causes the problems it does. “We show that intrathecal delivery motor defi cit mice had developed by said, “it would take a true pessimist to Previous attempts to silence the can achieve broad distribution, not the start of treatment, although not think that we can’t deliver the drug in mutant HD gene have employed virally- just in the spinal cord but in almost all to the level of wild-type animals. The an effective way to parts of the [human] delivered interfering RNA. Because of an brain regions, and reaches the major improvement was sustained for up to brain that are centrally involved in the abundance of virus receptors in brain brain regions that you would want nine months. There were also sustained disease. And that’s pretty good. It’s not tissue, most of the injected virus has to get to treat Huntington’s disease,” improvements in hypoactivity and anxi- perfect but it’s pretty good.” Based on been absorbed by a very small volume Dr. Cleveland said. ety, as measured by their willingness these results, Isis, the company that pro- of brain tissue immediately surrounding Mice bearing the mutant human HD to explore a lit arena. These improve- duces the oligo, is moving ahead with the injection site. gene were continuously infused with the ments developed slowly, and persisted plans for a clinical trial within two years.

‘It’s going to be high risk in terms of EXPERT COMMENTARY “One of the big surprises is that this its chances for success, but we think method seems remarkably effective” it’s well worth trying.’ at delivery, said Steven Finkbeiner, MD, PhD, director of the Taube- Koret Center for Huntington’s Disease Research and professor of neurology and physiology at the University of antisense oligo for two weeks, and then long after mutant huntingtin had been California, San Francisco, who was not the process was stopped. The oligo was restored to its pretreatment levels. involved with the study. “There does not detected in regions of the brain com- “This was perhaps the most surpris- seem to be reasonable confi dence that posed primarily of white matter. ing feature,” Dr. Cleveland said. “Our you can actually deliver the drug widely The level of oligo in the brain inference from that is that the reduction throughout the nervous system. The decreased steadily over the next 16 of huntingtin synthesis has allowed the other thing that’s really new is that you weeks. Human huntingtin mRNA was clearance of some toxic intermediate can get behavioral benefi ts that last quite reduced to 38 percent of control levels species that then take time to rebuild a bit longer than the measurable sup- immediately after the end of infusion, up, and that the anxiety [improvements] pression in the Huntington’s gene.” and continued to remain suppressed are measures of neuronal rewiring of the “Our conception of neurodegenera- DR. DON CLEVELAND: “We for the next 12 weeks, rising back remaining neurons, and that takes time.” tive disease has been hugely infl uenced show that intrathecal delivery to untreated levels over the next four “There remains a controversy about by pathologists,” he noted, leading to can achieve broad distribution, weeks. The level of mutant protein fol- how safe it will be to lower normal a primary emphasis on cell loss. The not just in the spinal cord but lowed a similar pattern. huntingtin” in humans, Dr. Cleveland results of this study combine with others in almost all brain regions, and To determine the ability of treatment said, so safety as well as effi cacy were suggest that, instead, “the defi cits you see reaches the major brain regions to reverse disease symptoms after they critical questions in the mouse. That are the consequence of ongoing dysfunc- that you would want to get to treat Huntington’s disease.” had developed, and to determine the transient suppression of the protein led tion triggered by mutant huntingtin, and duration of short-term treatment, the to prolonged symptomatic improvement Continued on page 11

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Antisense Treatment, It must also be shown that the required during development, but its Huntington’s Disease treatment is safe in humans. “I think role in the adult brain is unknown, REFERENCE: Continued from page 10 all of us feel there is going to be a with some researchers suggesting it • Kordasiewicz HB, Stanek minimum amount of protein lower- may be unnecessary. LM, Cleveland DW, et al. Sus- if you lower it, you have the possibility ing that is going to be necessary to But the bottom line, he said, is that tained therapeutic reversal of of recovering function that apparently have a therapeutic effect,” Dr. Pacifi ci “we’re very excited about the prospects” Huntington’s d isease by transient had been lost. To the extent that holds said, “but also a maximum beyond for antisense treatment in HD. “It’s going repression of huntingtin synthesis. in humans, that should affect the way we which you might end up getting del- to be high risk in terms of its chances Neuron 2012;74(6):1031-1044. think about neurodegenerative disease. eterious effects,” due to a reduction for success, but we think it’s well worth It suggests that at least some aspects of it in normal huntingtin. The protein is trying.” • may be reversible. Almost certainly the defi cits we see are the interplay between helpful and maladaptive changes the brain undergoes” to cope with the accu- mulation of mutant protein. The exact pathogenic cascade through which mutant huntingtin causes disease remains unclear, said Robert Pacifi ci, PhD, chief scientifi c offi cer of CHDI, a nonprofi t research organization dedicated to Huntington’s disease. “But if there is one therapeutic approach that really skirts these arguments, it is huntingtin lowering.” Both Dr. Finkbeiner and Dr. Pacifi ci were encouraged and excited about the prospects for a clinical trial. The key question in any clinical trial, Dr. Finkbeiner said, “is are you working on a validated target?” Whatever the downstream mechanisms, it is clear that in HD, the mutant protein is the ultimate validated target, and lowering it should be the initial effi cacy mea- sure in any trial of antisense therapy. “I think if you show that, I would be very committed to keep doing clinical trials,” even if symptomatic improvement is more diffi cult to demonstrate initially.

DR. STEVEN FINKBEINER: “There does seem to be reasonable conﬁ dence that you can actually deliver the drug widely throughout the nervous system. The other thing that’s really new is that you can get behavioral beneﬁ ts that last quite a bit longer than the measurable suppression in the Huntington’s gene.”

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