Early Study Identifies 3 Small Molecules That Target Root Cause of Huntington’s

Researchers have identified three new small molecules that significantly reduce the formation of toxic aggregates of mutant huntingtin — the underlying cause of Huntington’s disease — in cells derived from Huntington’s patients.

These molecules work by selectively and potently binding to the expanded CAG repeats in an intermediate molecule between the huntingtin (HTT) gene and the resulting huntingtin protein — making them promising therapeutic candidates for Huntington’s disease.

The study, “Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein,” was published in the journal Scientific Reports.

Huntington’s disease is caused by excessive (more than 36) repeats of a portion of DNA, called CAG triplets, within the HTT gene, which result in the production of an abnormal and toxic protein called mutant huntingtin (mHTT).

Increasing evidence suggests that, in addition to toxic mHTT, mutant HTT messenger RNA (mRNA) — the intermediate molecule generated from the mutant HTT gene that contains the instructions to produce the huntingtin protein — also contributes to Huntington’s development.

Over the past few years, several studies have identified a number of molecules that show promising therapeutic effects in cellular and animal models of Huntington’s disease. While some of them promote mHTT protein degradation, others such as Myricetin — a plant-based small molecule — target the expanded CAG triplets in mutant HTT mRNA.

A team of researchers in India had previously shown that Myricetin specifically targeted these abnormal CAG repeats in mRNA by binding to a specific region called the 5’CAG/3’GAC motif. Myricetin was also found to reduce mHTT’s toxic aggregation and ease behavioral symptoms in a mouse model of Huntington’s.

In the new study, the same team identified three new small molecules similar to Myricetin, but which seem to be safer and more effective in reducing mHTT production and the formation of toxic aggregates.

The researchers began by screening the National Cancer Institute database — which contains more than 250,000 compounds — for small molecules that could specifically target the expanded CAG triplets, based on the chemical structure of Myricetin.

The search identified 19 compounds with a similar structure to Myricetin. Further analyses using four different methods showed that three of them (CP2, CP6, and CP13) were highly specific and had a higher affinity to the 5’CAG/3’GAC mRNA motif than Myricetin.

The team then tested the therapeutic potential of these three lead molecules in a cellular model of Huntington’s disease and in cells derived from Huntington’s patients. Results showed that all three molecules were less toxic to cells than Myricetin, and significantly reduced the aggregation of mHTT, while improving cell survival.

These reductions in mHTT aggregation were different with each compound, “which could be due to the different mode of binding of the compounds or the mode of action and need to be studied in [the] future,” the researchers wrote.

Overall, the data highlighted that these three small molecules may be promising therapeutic candidates to reduce mHTT-associated damage in people with Huntington’s disease.

The team noted, however, that future studies are still required to evaluate these compounds in Huntington’s animal models and to determine their mechanism of action.