DNA repair emerges as a promising target
Scientists have understood, since the 1990s, that the number of excess CAG repeats measured in a blood test is not the sole predictor of the onset of motor symptoms or rate of progression of Huntington’s disease.
Since the early 2000s, researchers have also known that the number of CAG repeats in cells is unstable, both in different tissues and cell types, and over time. People with Huntington’s disease turned out to be genetic mosaics, with varying, changing lengths of CAG repeats in cells. Repeats increase as a person ages, most drastically in the spiny medium neurons of the brain.
The process by which CAG repetitions grow in cells, known as somatic instability, remained poorly understood and little investigated until 2015, when a genomewide association study revealed previously unknown mechanisms.5 As it turns out, genes involved in the growth of CAG repeats are related to the DNA mismatch repair pathway, which is also important in cancer.
DNA mismatch repair refers to a complex housekeeping system, involving multiple genes and enzymes, that is fundamental to the functioning of the body as genes are continuously being translated to form proteins. Mismatch repair becomes increasingly error-prone with age: Mistakes that are not repaired become mutations, some of which are irrelevant and others that can be deleterious and lead to cancer.
In Huntington’s disease, enzymes involved in repairing DNA are the same ones that can erroneously add CAG repeats to HTT. A person with Huntington’s disease inherits what can be considered a “dyslexic” DNA repair system, Dr. Sampaio said, that misreads its template and keeps adding CAGs.
After the 2015 genomewide association study, “the DNA mismatch repair pathway became hugely important in Huntington’s disease research, and there is a lot of attention being paid now to its components. The idea is that, if we can intervene in this process, we might stop the somatic instability, the growing of the CAG repetitions, and ameliorate the progression of the disease,” Dr. Sampaio said.
In 2017 Dr. Tabrizi’s team reported that the mismatch repair gene MSH-3 was as a key driver of CAG repeats in people with Huntington’s disease.6 “I’m working really closely now with DNA repair scientists who’ve been working in cancer for 20 years. Cancer and repeat expansion diseases have really come together,” Dr. Tabrizi said.
At CHDI’s April 2023 therapeutics conference in Dubrovnik, Croatia, scientists presented findings on how to target MSH-3 and other mechanisms that underlie somatic instability.7 (Several drug companies are working on small molecules, ASOs, and other ways to inhibit MSH-3.) Researchers also presented extensively on protein lowering. The two treatment strategies are compatible for Huntington’s disease, Dr. Tabrizi said.
“I think the best way to approach Huntington’s is to target the somatic CAG repeat expansion by inhibiting MSH-3 in some way, and also target HTT lowering – but targeting it at the DNA level, as opposed to clearing the protein,” Dr. Tabrizi said. DNA-centered approaches in preclinical testing include CRISPR gene editing to inactivate mutant HTT and zinc finger proteins that allow selective targeting of DNA to reduce mutant HTT.
Recent findings on the mismatch repair pathway in Huntington’s disease have direct implications for other rare neurologic diseases caused by triplet repeat mutations, including myotonic dystrophy and cerebellar ataxias.
“There is very strong basic fundamental research in Huntington’s disease that doesn’t exist for every disease,” Dr. Sampaio said. “The fact that it is monogenic, and an adult disease that progresses relatively slowly, has made it a good disease to study, a kind of model.”
Huntington’s disease research has also generated research strategies of value in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. It provided key insights about neurofilament light, a biomarker of neuronal damage, and about the ASO drug class, which is being investigated for its utility treating in a range of diseases.
Previously, Huntington’s disease trial cohorts and registries focused on patients with late symptomatic disease. However, researchers are now pivoting to patients with less-severe disease and to preclinical mutation carriers. “We now know you have to treat early,” Dr. Tabrizi said. “This has implications for the whole field.”
Dr. Sampaio disclosed that she is an employee of CHDI Management, the administrative arm of the CHDI foundation. Dr. Tabrizi disclosed serving as a consultant to Alnylam Pharmaceuticals, Annexon, Ascidian Therapeutics, Arrowhead Pharmaceuticals, Atalanta Therapeutics, Design Therapeutics, F. Hoffmann-La Roche, HCD Economics, IQVIA, Iris Medicine, Latus Bio, LifeEdit, Novartis, Pfizer, Prilenia Therapeutics, PTC Therapeutics, Rgenta Therapeutics, Takeda Pharmaceuticals, uniQure, and Vertex Pharmaceuticals.