Cancer Therapy Bexarotene Shows Early Promise in Treating Huntington’s, Mouse Study Finds

Researchers have found that bexarotene, an existing, approved drug used to treat cancer, may also be an effective therapy for Huntington’s disease.

The study, “PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis,” appeared in the journal Science Translational Medicine.

Researchers used cellular models of Huntington’s disease and a Huntington’s mouse model. Treatment with bexarotene, a drug used in cutaneous T-cell lymphoma, led to improved motor function and recovery from neurodegeneration. The mice were also able to live longer.

The findings add to a previous study from the same research team, which showed that the drug KD3010 is an effective treatment for Huntington’s in a mouse model and in neurons from human patients.

“It’s not just the response from the drugs, but the mechanistic pathways these drugs are targeting,” Al La Spada, an MD and PhD, the study’s senior author, said in a press release.

La Spada is the chief of the Division of Genetics in the Department of Pediatrics at UC San Diego, and the 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,” he said.

Both bexarotene and KD3010 activate the peroxisome proliferator-activated receptor gamma (PPAR), a molecule located in the cellular nucleus that regulates gene expression (the production of proteins from DNA). PPAR gamma contributes to the health and correct functioning of mitochondria (the powerhouses of cells), and helps neurons remove dysfunctional proteins.

The activation of PPAR gamma is impaired in Huntington’s patients. La Spada’s team showed that treatment of mice with bexarotene improved both mitochondrial health in neurons and the clearance of damaging proteins. The effects were observed in mouse neurons in vitro and in vivo, as well as in human neurons derived from Huntington’s patients.

No existing medications are able to slow or stop the progression of Huntington’s disease. Despite the promising results, additional research is needed before using bexarotene or KD3010 in people with Huntington’s. High dosages of bexarotene can induce serious side effects. And testing of KD3010 in humans is still restricted to type 2 diabetes.

The research team found that the combination of bexarotene and KD3010 led to a greater therapeutic benefit. This suggests that future therapies for Huntington’s disease may involve combined medications, as in the treatment of HIV.

“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 Audrey Dickey, PhD, the study’s lead author.

The findings also suggest the drug may be beneficial in other neurodegenerative diseases.

“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,” Dickey added.