C2-8 Slows Progression in HD Mice

HD Lighthouse Contributing Editor's Comment: C2-8, a promising compound identified in a high throughput assay in the Drug Discovery Lab at the Massachusetts General Institute for Neurodegenerative Disease, has continued to move successfully through the research pipeline.

In Parts One and Two of this series, we discussed how C2-8 was found to inhibit the aggregation of the HD protein and rescue photodegeneration in a drosophilia model of HD.

Steven Hersch and the research team has followed up by testing the compound in the R6/2 HD mice with good results.  The compound penetrated the blood brain barrier, improved symptoms, and reduced neurological damage.  

The drug clearly addresses some of the pathologies of the mouse but did not prolong life. They may be able to develop the drug further or test a related drug which will be able to do so. However, that may not be necessary for the drug to have therapeutic value.

Huntington's Disease is a multi-hit disease. The original cause is known, the expanded CAG repeats in the mutated form of the gene, but those repeats cause a cascade of problems. It may be that the pathway(s) to cellular dysfunction are different than the pathway to cell death. C2-8 or a related compound may eventually become part of combination therapy.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 01-01-2008

Steven Hersch, M.D., Ph.D.

A small-molecule therapeutic lead for Huntington's disease: Preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse.

Vanita Chopra, Jonathan H. Fox, Greg Lieberman, Kathryn Dorsey, Wayne Matson, Peter Waldmeier, David E. Housman, Aleksey Kazantsev, Anne B. Young, and Steven Hersch

the press release

BOSTON - October 8, 2007 MassGeneral Institute for Neurodegenerative Disease researchers have identified a compound that may lead to a treatment that could protect against the effects of Huntington's Disease (HD). Their report, which will appear in the Proceedings of the National Academy of Sciences, describes how a small molecule called C2-8 appears to delay the loss of motor control and reduce neurological damage in a mouse model of the disorder. The study is receiving early online release.

"We found that C2-8 slows the progress of HD in a mouse model and might do the same thing in human patients, if it or its biochemical relatives can be translated into a drug," says Steven Hersch, MD, PhD, of MIND and the Massachusetts General Hospital (MGH) Department of Neurology, who led the study. "What we don't know yet is precisely how it works, what molecules it interacts with in cells and how potent it might be."

C2-8 was first identified as a candidate treatment for HD by MIND researcher Aleksey Kazantsev, PhD, based on its ability to block the aggregation of the mutant huntingtin protein in yeast and animal tissue and to improve function in a fruit fly model. The current study was designed to further investigate its potential as a therapeutic drug. The researchers first confirmed that oral doses of C2-8 can cross the blood-brain barrier and are nontoxic in a mouse model of HD. They also found that C2-8 does not interact with a number of molecules predictive of negative side effects.

HD mice that were treated with C2-8 starting at the age of 24 days scored significantly better on tests of strength, endurance and coordination than did HD mice that did not receive the molecule. While treatment significantly delayed progressive motor disability, the animals receiving C2-8 did not live longer. Examination of brain cells from the striatum, the area of the brain where the deterioration of HD occurs, showed that treated mice had less shrinkage of brain cells and smaller aggregates of huntingtin protein than did untreated HD mice.

"We've both validated that compounds reducing the aggregation of mutant huntingtin are potential HD drugs - so that strategy is one that other scientists should pursue - and shown that C2-8 has potential as the basis of a neuroprotective treatment," says Hersch. "We now need to confirm those results in a different mouse model, see whether similar compounds may be more potent than C2-8 and search for the molecules it targets." Hersch is an associate professor of Neurology at Harvard Medical School.

Vanita Chopra, PhD, and Jonathan Fox, PhD, of MIND and MGH-Neurology are co-first author of the PNAS study. Additional co-authors are Greg Lieberman, Kathryn Dorsey, Kazantsev and Anne B. Young, MD, PhD, of MIND/MGH-Neurology; Wayne Matson, PhD, Boston University School of Medicine; Peter Waldmeier, PhD, Novartis Institute for Biomedical Research, Basel, Switzerland; and David Houseman, PhD, Massachusetts Institute of Technology. The study was supported by the Discovery of Novel Huntington's Disease Therapeutics Fund, MIND and the Massachusetts General Hospital.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.

the abstract

Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine expansion within huntingtin protein. The exact pathological mechanisms determining disease onset and progression remain unclear. However, aggregates of insoluble mutant huntingtin (mhtt), a hallmark of HD, are readily detected within neurons in HD brain. Although aggregated polyglutamines may not be inherently toxic, they constitute a biomarker for mutant huntingtin useful for developing therapeutics.

We previously reported that the small molecule, C2-8, inhibits polyglutamine aggregation in cell culture and brain slices and rescues degeneration of photoreceptors in a Drosophila model of HD. In this study, we assessed the therapeutic potential of C2-8 in the R6/2 mouse model of HD, which has been used to provide proof-of-concept data in considering whether to advance therapies to human HD. We show that, at nontoxic doses, C2-8 penetrates the blood-brain barrier and is present in brain at a high concentration. C2-8-treated mice showed improved motor performance and reduced neuronal atrophy and had smaller huntingtin aggregates.

There have been no prior drug-like, non-toxic, brain-penetrable aggregation inhibitors to arise from cell-based high-throughput screens for reducing huntingtin aggregation that is efficacious in preclinical in vivo models. C2-8 provides an essential tool to help elucidate mechanisms of neurodegeneration in HD and a therapeutic lead for further optimization and development.

Source: Proceedings of the National Academy of Sciences USA. Published online before print October 9, 2007