Progress Stirs for the Treatment of Huntington Disease


At least 2 agents are being looked at as possible treatments for Huntington disease: eicosapentaenoic acid (EPA) and a poly (ADP-ribose) polymerase (PARP1) inhibitor termed K245-14.

At least 2 agents are being looked at as possible treatments for Huntington disease (HD). One therapeutic possibility is eicosapentaenoic acid (EPA), marketed as Miraxion by Amarin Corporation; the other is a poly (ADP-ribose) polymerase (PARP1) inhibitor termed K245-14. The former has anti-inflammatory and neuroprotective properties1; the latter conserves energy in cells by putting the breaks on aggressive PARP1-mediated adenosine triphosphate (ATP) depletion in the environment of huntingtin gene mutation.2 Both are promising breakthroughs for this devistating disease that affects motor function, cognition and mood.


Research reported at the annual meeting of the American Academy of Neurology in San Diego last April revealed that EPA increased expression of cytokine interleukin (IL)-10 and decreased expression of prosta- glandin E2 in a rodent model of neuroinflammation.1 The researcher, Cai Song, MD, PhD, associate professor and Canada Research Chair in Psychoneuroimmunology at the University of Prince Edward Island in Charlottetown, demonstrated that learning ability, memory, nerve growth factor expression, and IL-10 production improved and prostaglandin E2 production decreased after 7 weeks of administration of EPA to rats rendered into experimental models by exposure to cytokine IL-1ß. "EPA incubation with neurons largely increased neuronal proliferation and blocked lipopolysaccharide- or glutamate-induced cortical cell death," she reported, concluding that EPA might be a therapeutic option for the treatment of neurodegenerative diseases.

A phase 3 European trial of EPA for the treatment of HD has just completed enrollment. The trial's execution will include 27 leading neurology centers in Austria, Germany, Italy, Portugal, Spain, and the United Kingdom. The hope is that a 6-month course of the agent at a dosage of 1 g bid will result in significant improvements in motor function as measured on the Total Motor Score-4 subscale of the Unified Huntington's Disease Rating Scale.

EPA has orphan drug status in the United States and Europe, and its FDA new drug application has been given fast track status.


"It has recently been shown that neurons from patients with [HD] appear to be energy-deficient, so we hypothesized that modest stresses that would be tolerated by healthy cells could send HD cells below a viable energy threshold and that blocking PARP1 activation could be protective," said Aleksey Kazantsev, PhD, in a statement to the press. A team led by Kazantsev, who is the director of the MIND High Throughput Drug Screening Laboratory at Massachusetts General Institute for Neurodegenerative Diseases in Boston, performed a search for small molecules that could be potential PARP1 inhibitors. They found 2: CG1 and K245-14. When both molecules were put to the test in cultured human and rat cells, K245-14 prevented apoptosis of cells in which PARP1 had been overactivated.

The investigators then sought to establish whether K245-14 could reduce energy depletion in cells marked by the huntingtin gene mutation. The investigators were able to confirm that, as expected, oxidative stress resulted in ATP loss. More important, they established that cells affected by HD, which had significantly lower ATP levels compared with normal cells at baseline, were significantly more vulnerable to stress-induced energy loss. Notably, treating the cells with K245-14 consistently reduced ATP loss and had a significant protective effect against both energy loss and cell death.

Kazantsev and coauthors called for initiation of studies to test K245-14 in preclinical models of HD and other neurodegenerative diseases. His team at Massachusetts General Hospital and Harvard University plan to work with coinvestigators from The Scripps Research Institute in La Jolla, California, to identify more potential PARP1 inhibitors.


1. Song C. Therapeutic mechanism of n-3 fatty acid EPA in treatment of neurodegeneration: anti-inflammation and neuroprotection. Neurology. 2006;66(suppl 2):A284.

2. Altmann SM, Muryshev A, Fossale E, et al. Discovery of bioactive small-molecule inhibitor of poly ADP-ribose polyermase: implications for energy-deficient cells. Chem Biol. 2006;13:765-770.

Related Videos
medical student
fish river
© 2024 MJH Life Sciences

All rights reserved.