Medication used to treat cancer could potentially be an effective therapy for Huntington's disease, according to new research led by Duke University School of Medicine in Durham, NC. The drug may also offer a pathway to treat other neurodegenerative diseases.
Dr. Albert La Spada, director of the Duke Center for Neurodegeneration and Neurotherapeutics, conducted the study with colleagues from several other institutes.
These included Duke University's Department of Neurobiology, the University of California, San Diego, the Salk Institute for Biological Sciences in La Jolla, CA, and the Johns Hopkins School of Medicine in Baltimore, MD.
Their findings were published in the journal Science Translational Medicine.
Huntington's disease is an inherited disorder that leads to the degeneration of certain nerve cells in the brain. The condition is progressive and affects movement, cognition, and behavior.
There is no cure for Huntington's disease and no therapies to stop or slow down its progression. People with Huntington's often die within 15 to 20 years of being diagnosed.
Previous research by Dr. La Spada and his colleagues found that a compound known as KD3010, tested in the treatment of diabetes, was effective in reducing disease progression and overall neurodegeneration and improving motor function in a mouse model of Huntington's disease.
Drug removed damaged proteins
Mice that the researchers treated with bexarotene became more mobile, showed signs of recovery from neurodegeneration, and lived for longer.
Dr. La Spada notes that the results of the study are not just exciting because the drug worked, but also due to how they worked.
"It's not just the response from the drugs, but the mechanistic pathways these drugs are targeting," says Dr. La Spada. "These pathways are relevant to other neurodegenerative disorders and potentially the aging process, itself in addition to Huntington's disease."
Bexarotene and KD3010 work by activating PPARδ, which is a transcription factor tasked with maintaining neuron functionality. It does so by keeping mitochondria active and healthy, and enabling neurons to remove faulty proteins.
Both mice and humans with Huntington's disease face problems with the activation of PPARδ. When the researchers treated the mice with Huntington's disease with bexarotene or KD3010, they showed an improvement in mitochondrial health in neurons and a rise in the deletion of misfolded proteins.
Mitochondrial function impairment and protein misfolding are factors that also play a vital role in other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).
Although the findings are promising, they do not mean that individuals with Huntington's disease should immediately rush out to get bexarotene or KD3010.
Future research will first need to determine how these drugs could be used in humans. Optimal doses of bexarotene are currently unknown, and the drug causes significant side effects at high doses. KD3010 has only been tested in type 2 diabetes.
'Cocktail approach' may be more effective
The team suggests that future therapies for Huntington's disease and other neurodegenerative conditions may involve a "cocktail" approach, by combining medications in a similar way to the treatment of HIV.
Lead study author Audrey Dickey, Ph.D., reveals that when bexarotene and KD3010 were taken together, better results were seen in cells — even at low 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."
Audrey Dickey, Ph.D.
She concludes that the team is "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."