Existing cancer medication offers potential to treat Huntington's disease

December 6, 2017, Duke University
A montage of three images of single striatal neurons transfected with a disease-associated version of huntingtin, the protein that causes Huntington's disease. Nuclei of untransfected neurons are seen in the background (blue). The neuron in the center (yellow) contains an abnormal intracellular accumulation of huntingtin called an inclusion body (orange). Credit: Wikipedia/ Creative Commons Attribution 3.0 Unported license

A drug already used to treat certain forms of cancer may also be an effective therapy for Huntington's disease, according to a new study in the latest issue of Science Translational Medicine. The same study also increases our understanding of how this drug, and other medications like it, may offer hope for other neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease.

Huntington's is a devastating, inevitably fatal disease, with no medications that slow or stop disease progression. 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 same research builds on a 2016 study where La Spada and his team showed that the KD3010 is an effective treatment for Huntington's disease in mice and in human patient neurons made from stem cells.

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."

Bexarotene and KD3010 function by activating PPARδ, a transcription factor that keeps neurons functional in two ways: by keeping mitochondria healthy and active, and by helping neurons remove dysfunctional proteins. Mice—and humans—with Huntington's disease have problems activating PPARδ. When La Spada and colleagues treated Huntington's mice with bexarotene or KD3010, they observed improved mitochondrial health in neurons, as well as increased removal of damaging misfolded proteins.

The same factors of impaired mitochondrial function and protein misfolding are recognized as increasingly important in diseases like Alzheimer's disease, Parkinson's disease, and ALS.

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.

Instead, future therapies for Huntington's disease and other neurodegenerative conditions may take a cue from HIV treatments and involve a "cocktail" approach of combined medications. Lead author Audrey Dickey, PhD, found that, taken together, 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."

Explore further: Existing compound holds promise for reducing Huntington's disease progression

More information: Audrey S. Dickey et al, PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis, Science Translational Medicine (2017). DOI: 10.1126/scitranslmed.aal2332

Related Stories

Existing compound holds promise for reducing Huntington's disease progression

December 7, 2015
Currently, there is no treatment to halt the progression of Huntington's disease (HD), a fatal genetic disorder that slowly robs sufferers of their physical and mental abilities. Now, researchers at University of California, ...

Potential therapeutic target for Huntington's disease

August 16, 2016
There is new hope in the fight against Huntington's disease. Scientists at the Gladstone Institutes discovered that changing a specific part of the huntingtin protein prevented the loss of critical brain cells and protected ...

Cellular quality control process could be Huntington's disease drug target

February 13, 2017
The loss of motor function and mental acuity associated with Huntington's disease might be treatable by restoring a cellular quality control process, which Duke Health researchers have identified as a key factor in the degenerative ...

Two proteins offer a 'clearer' way to treat Huntington's disease

July 11, 2012
In a paper published in the July 11 online issue of Science Translational Medicine, researchers at the University of California, San Diego School of Medicine have identified two key regulatory proteins critical to clearing ...

Discovery could aid in development of treatments for fatal brain disease

April 9, 2017
Huntington's disease is an inherited brain disorder that is uniformly fatal, but researchers at Johns Hopkins believe they have made a big discovery about how the disease progresses that could lead to a way to stop it.

Huntington's disease alters neurons from development

March 21, 2017
Huntington's disease could alter neurons from when they start developing, according to a study conducted by the international HD iPSC Consortium. The study was published in the scientific journal Nature Neuroscience.

Recommended for you

Researchers unravel why people with HIV suffer from more neurologic diseases

August 20, 2018
Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), which the HIV virus can cause, continue to be one of the world's greatest health problems.

Fluidically linked blood-brain barrier and Organ Chips offer new method for studying effects of drugs on the brain

August 20, 2018
The human brain, with its 100 billion neurons that control every thought, word, and action, is the most complex and delicate organ in the body. Because it needs extra protection from toxins and other harmful substances, the ...

Female mice are immune to cognitive damage from space radiation

August 20, 2018
Humankind still dreams of breaking from the bounds of Earth's atmosphere and venturing to the moon, Mars and beyond. But once astronauts blast past the International Space Station, they become exposed to one of the many dangers ...

Children with brain tumors who undergo radiation less likely to recall recent events

August 20, 2018
Children with certain types of brain tumors who undergo radiation treatment are less likely to recall the specifics of events they experienced after radiation than to remember pre-treatment happenings, according to a Baylor ...

Rogue proteins may underlie some ALS and frontotemporal dementia cases, says study

August 20, 2018
ALS—amyotrophic lateral sclerosis—is a neurodegenerative disease that attacks motor neurons in the brain and spinal cord, slowly robbing its victims of their ability to walk, talk, breathe and swallow. In a cruel twist, ...

Bilingual children who speak native language at home have higher intelligence

August 20, 2018
Children who regularly use their native language at home while growing up in a different country have higher IQs, a new study has shown.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.