Huntington’s Researchers Identify Novel Compound in Search for Potential Treatment Strategy

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by Magdalena Kegel |

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Huntington's, new therapeutic targets

Researchers at Massachusetts General Hospital (MGH) report they’ve identified a novel compound that could be a potential therapy strategy for Huntington’s disease, protecting nerve cells from death in both cultured cells and animal models of the disease.

The study, SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington’s Disease Models, available in an early online publication in the journal Cell Chemical Biology, demonstrated that the newly identified compound exerted its actions on the brain through two distinct mechanisms — improving the chances that a potential drug will be effective in Huntington’s patients.

The senior author of the study, Aleksey Kazantsev, PhD, from MassGeneral Institute for Neurodegenerative Disorders (MIND), said in a news release that research increasingly supports that mechanisms behind neurodegenerative diseases, such as Huntington’s, are very complex — a fact that minimizes the likelihood that a drug with a single mechanism of action might be effective.

“The lead compound identified in the current study has two distinct mechanisms, both of which are shown to be potentially neuroprotective and which we expect will have synergistic benefits,” he said.

The new study builds on earlier research from the MIND lab, showing that a molecule called SIRT2 could be involved in Huntington’s. Together with researchers at 12 other centers in five countries, the team started looking for molecules that could potentially block SIRT2.

Among several candidates, they chose to continue their efforts with the most potent blocker, naming it MIND4. Studying the effects of the drug candidate in cultured cells in the lab, as well as in Huntington’s animal models, they discovered that one of the main actions of MIND4 was to block oxidative stress pathways, mediated by another molecule called NRF2.

Surprisingly, they found that boosting the activity of NRF2 did not depend on the drug’s ability to block SIRT2. The studies also showed that MIND4 protected both rat and fruit fly models of Huntington’s disease from neurodegeneration.

Researchers stated that although they can’t ascribe the neuroprotective effect of the drug to any of the two mechanisms, they speculate that both are needed to achieve this beneficial effect.

“MIND4 is a great starting template for drug development, and we have promising preliminary results in two mouse models. We also need to optimize the pharmacology to meet FDA (U.S. Food and Drug Administration) requirement for a version we can test in human patients,” Kazantsev said.