Treatments for Huntington’s disease have shown promise in clinical trials. The hallmark for measuring the disease is CAG repeats. Beth Hoffman, Chief Executive Officer of Origami Therapeutics, used phenotypic screening in primary human fibroblasts to identify small molecules that prevent mutant Huntington protein aggregation. Specifically, she highlighted the importance of physiologically relevant models and high-content imaging.
Reducing the mutant Huntington leads to reversal of the disease in several animal models. Evidence from other scientific papers shows that whether using a genetic switch to turn a gene on or off, or attacking it through RNA degradation or protein degradation, all of these methods halt and reverse HD symptoms.
This information is crucial since it gives insights into how to attack the problem. Huntington is a scaffold protein and, as such, interacts with several different proteins. HD is a protein folding disorder, and the mutant Huntington tends to misfold; as a result, this causes mislocalisation, aggregation, and a change in biological activity.
Hoffman explained that when designing a screen, there are several key factors to consider, the main one being selecting an endpoint that could report on protein misfolding. She used aggregation as an indication of misfolding.
The screen identified around 73 hits from around 100,000 compounds. 60 of them showed emerging SAR. The identified compounds, particularly ORI-113, selectively reduced mutant Huntington protein and its toxic fragments in both fibroblasts and neurons, with minimal effect on wild-type protein. She added the Branaplam and siRNA, both of which target mRNA to reduce full-length mutant and wild-type HTT, but are ineffective against the mutant HTT fragments.
The compounds improved autophagosome formation, reversed disease phenotypes in patient-derived neurons, and normalized transcriptomic and proteomic differences. Overall, this suggests restoration of cellular balance.
In an in vivo study, ORI-113 lowered MHTT protein in a transgenic HD model. It demonstrated brain penetrance and led to a significant reduction of mutant Huntington in key brain regions like the striatum and cortex without adverse effects. Additionally, there was no change in exposure over 14 days.
