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Cancer Drug Could Offer Potential Treatment for Huntington’s disease

Researchers studying neurodegenerative diseases have now found a novel potential treatment for Huntington’s disease (HD), a form of neurodegenerative disease that impairs a person’s physical and mental abilities.

The study has shown that an anti-cancer drug called bexarotene could treat HD in cellular models of HD as well as in an HD mouse model. Furthermore, the study has provided clearer insights into how bexarotene works. These discoveries will have implications for treatment of not only HD but also other forms of neurodegenerative diseases.

Senior author Al La Spada, MD, PhD, (photo) said the study results are exciting not just because these drugs worked, but because of how they worked. “It’s not just the response from the drugs, but the mechanistic pathways these drugs are targeting,” said La Spada, director of the forthcoming Duke Center for Neurodegeneration and Neurotherapeutics. “These pathways are relevant to other neurodegenerative disorders and potentially the aging process, itself in addition to Huntington’s disease.

In this study, mice with the equivalent of Huntington’s disease became more mobile, recovered from neurodegeneration, and lived longer after being treated with bexarotene.

The peroxisome proliferator–activated receptors (PPARs) are ligand-activated transcription factors that

promote mitochondrial biogenesis and oxidative metabolism.

The current research builds on a 2016 study where La Spada and his team showed that the drug KD3010 is an effective treatment for Huntington’s disease in mice and in human patient neurons made from stem cells. Previously, Dr. La Spada and his team demonstrated in mouse models of HD that “pharmacologic activation of PPARδ, using the agonist KD3010, improved motor function, reduced neurodegeneration, and increased survival.”

In the new study, Dr. La Spada and his team tested the effect of bexarotene, an FDA-approved drug that is used to treat cancer and seems to promote PPARδ activation. Using cellular models of HD, they found that bexarotene was neuroprotective. Using a mouse model of HD, they discovered that like KD3010, bexarotene improved motor function, reduced neurodegeneration, and increased survival. Further investigation provided insights into the working mechanisms of bexarotene: the drug activated PPARδ to improve mitochondrial function and cellular quality control.

Cancer Drug Could Offer Potential Treatment for Huntington’s disease
Senior author Al La Spada

The study doesn’t mean that patients with Huntington’s disease or other conditions should rush to get bexarotene or KD3010. Further research needs to determine how to use these drugs in human patients. Bexarotene can have difficult side effects at high dosages, and optimal doses aren’t known, while KD3010 has only been tested in human subjects for type II diabetes.

Lead author Audrey Dickey, PhD, found that, taken together, bexarotene and KD3010 produced better results in cells even when given at lower doses.

With this approach, we could minimize side effects with lower doses of each compound, even when together the treatments provide a higher effect than either one alone,” said Dickey. “We are carrying out further research on the underlying mechanisms of neuroprotection and applying this research to other diseases with similar issues of mitochondrial dysfunction and protein quality control, such as Parkinson’s disease, Alzheimer’s disease, and ALS.

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