Neurology Central

Well-tolerated compound holds potential hope for the treatment of Huntington’s disease

In a new study, published recently in Nature Medicine, researchers have presented findings highlighting a compound termed KD3010 as a potentially effective treatment for slowing Huntington’s disease (HD) symptoms and decline. The compound was previously tested for use in the treatment of diabetes in a Phase Ib trial where it was well-tolerated in participants.

“We’re very excited by our preclinical testing of this compound (KD3010),” commented lead author Albert La Spada (University of California, San Diego, USA).

Following previous discovery of the significant role of PGC-1 alpha, a regulatory protein central to the creation and operation of mitochondria, as well as the ability of healthy cells to degrade damaged molecules, La Spada and his team sought to delve deeper into reduced PGC-1 alpha activity in their current study. Specifically, the team focussed on the evaluation of key transcription factors that rely upon PGC-1 alpha in order to function.

One transcription factor analyzed, termed peroxisome proliferator-activated receptor delta (PPARδ), indicated physical interaction with the huntingtin protein within the brains of HD mice. The function of PPARδ was also greatly impaired in HD nerve cells.

Subsequent to this, mutant PPARδ mice were bred to define their role in optimal neuron functioning. The mutant PPARδ was designed to turn off, consequently reducing energy production and degradation of misfolded proteins in nerve cells. “These mice developed very severe symptoms of Huntington’s disease,” explained La Spada.

Given the mechanism of KD3010, in increasing PPARδ activity, they then began to test the compound in HD mice, finding significant improvements in lifespan (16%) and in neurodegeneration. Mitochondrial energy production was also improved, as well as the removal of misfolded proteins.

“We have a drug that was FDA approved for human use in a clinical trial. It did not produce any significant side effects. This means it has a good safety profile and so likely can be moved into testing in Huntington’s patients much more quickly than compounds that have not been tested in humans. This is important since right now there is zero that can be done to alter the progression of this devastating disease,” commented La Spada.

La Spada and colleagues are now consulting with other HD research teams with regards to clinical trial design for KD3010 in HD, which they hope to commence within 18 months. Due to the role of misfolded proteins in other neurodegenerative disorders such as Alzheimer’s and Parkinson’s, they also hope that, if successful in HD, KD3010 could be tested for efficacy in the treatment of other key neurological diseases.

Source: University of California, San Diego press release