For decades, Huntington’s disease research has focused on one goal: lowering levels of the toxic huntingtin protein. The strategy made intuitive sense; the disease is caused by an expanded CAG trinucleotide repeat in the HTT gene that produces a misfolded, aggregation-prone protein, but the most prominent huntingtin-lowering therapy, tominersen, was halted in a Phase 3 trial in 2021 after making patients worse.
Now a growing body of evidence points to a fundamentally different target: not the protein itself, but the DNA repair machinery that gradually lengthens the CAG repeat within neurons over time. At the center of this emerging paradigm is MSH3, a protein in the DNA mismatch repair pathway that drives what researchers call “somatic expansion,” the slow, cell-type-specific growth of the inherited repeat that correlates far more closely with disease onset and progression than the repeat length measured at birth.
“The field is having a genuine paradigm shift,” said Steven McCarroll, a geneticist at the Broad Institute and Harvard Medical School whose lab published a landmark Cell paper in 2025 that mapped CAG expansion at single-neuron resolution. “The inherited repeat is the starting point. What kills the cell is how fast that repeat grows over time.”
A two-stage molecular cascade
McCarroll’s group showed that the CAG repeat in the HTT gene of striatal medium spiny neurons, the cell type most vulnerable to Huntington’s pathology, does not remain static. The researchers sequenced the repeat length in thousands of individual neurons and found a consistent pattern. Neurons carrying 40 to 80 CAG repeats appeared biologically quiet. At approximately 80 repeats, expansion accelerated sharply, “like going over a waterfall,” McCarroll described. At around 150 repeats, neurons entered a brief toxic phase and died within months.
The key driver of this expansion is MSH3, which forms a heterodimer with MSH2 (the MutS-beta complex) that recognizes the hairpin-shaped DNA structures formed by CAG repeats. In a normal cell, the mismatch repair system corrects such structures. In a Huntington’s neuron, the repair process goes awry and adds extra CAG copies. A competing nuclease, FAN1, normally counteracts MSH3 by binding MLH1 and blocking expansion, but when MSH3 levels are high or FAN1 is deficient, the expansion accelerates.
The cell-type specificity is striking. Striatal interneurons and glial cells rarely show CAG expansion, explaining why medium spiny neurons, which express MSH3 at elevated levels, are selectively vulnerable.
The MSH3 validation chain
The evidence linking MSH3 to Huntington’s progression runs through multiple independent lines. Human genetic studies have shown that naturally occurring variants in the MSH3 gene modify the rate of disease progression (Moss et al., Lancet Neurology, 2017). Knocking out Msh3 in a Huntington’s mouse model (the zQ175 line carrying approximately 185 CAG repeats) prevents further expansion and blunts motor decline (Bates et al., Brain, 2024).
The most direct therapeutic evidence comes from work by Sarah Tabrizi’s group at University College London, published in Science Translational Medicine in 2025. In iPSC-derived striatal neurons from Huntington’s patients, an MSH3-targeting antisense oligonucleotide showed a clear dose-response: a 41% reduction in MSH3 halves the expansion rate; an 83% reduction halts it entirely.
Researchers at UMass Chan Medical School have independently confirmed these findings using short interfering RNAs (siRNAs) to silence MSH3 in Huntington’s mouse models.
Enter Latus Bio
The translational baton has now been picked up by Latus Bio, a Philadelphia-based startup that raised a $97 million Series A round in May 2026. Its lead candidate, LTS-201 (AAV.DB3.miMSH3), is a one-time adeno-associated virus (AAV) gene therapy that delivers an engineered microRNA designed to knock down MSH3 expression in the striatum and cortex.
The therapy uses a proprietary capsid variant, AAV-DB3, engineered for potent and specific transduction of medium spiny neurons and cortical projection neurons after deep-brain or intracerebroventricular administration. Latus Bio plans to submit an Investigational New Drug application to the FDA in the third quarter of 2026.
Computational modeling presented at the American Society of Gene and Cell Therapy meetings in 2025 and 2026 predicts that early administration of an MSH3-targeting therapy, before symptom onset when the CAG repeat is still relatively short, could delay motor symptom onset by more than a decade, with the magnitude of MSH3 suppression being the primary efficacy driver.
Caveats: balancing benefit and cancer risk
The most significant concern with MSH3 suppression is cancer risk. MSH3 is part of the mismatch repair system that guards against certain cancers; complete loss-of-function in humans is linked to intestinal polyps and colorectal cancer. However, heterozygous carriers (with approximately 50% reduction in MSH3) appear healthy, and up to one year of MSH3 silencing in mice showed no obvious harm. RNA-seq in treated cells showed no disruption of other DNA repair pathways or oncogenic signaling even at more than 95% knockdown.
A second caveat emerged from the Bates lab’s mouse work: in animals with very long repeats, Msh3 knockout prevented further expansion but did not affect huntingtin aggregation or striatal transcriptional dysregulation. The implication is that early treatment is essential; once repeats are already very long, stopping further expansion may be necessary but not sufficient.
“There is good reason to think a combination approach will be needed,” said Jang-Ho Cha, chief scientific and medical officer of Latus Bio. “First freeze the expansion, then clear the toxic huntingtin protein. Each must be validated independently, but the field is moving toward a two-punch strategy.”
The company’s timeline places it in a competitive landscape that already includes Skyhawk Therapeutics’ oral small molecule SKY-0515 (now in Phase 1/2) and uniQure’s huntingtin-lowering gene therapy AMT-130 (accepted for FDA accelerated review in June 2026). The first MSH3-targeted company, Triplet Therapeutics, shut down in 2022 after investor confidence was shaken by tominersen’s failure.
For the approximately 41,000 symptomatic Huntington’s patients in the United States and more than 200,000 at-risk individuals, the shift from huntingtin to repeat expansion represents a new scientific horizon. Whether the therapeutic strategy can follow is a question the next few years will answer.
Sources
Handsaker RE, et al. “Single-cell CAG repeat sequencing reveals somatic expansion and tipping points in Huntington’s disease.” Cell (2025).
Bunting EL, et al. “MSH3 suppression halts CAG repeat expansion in patient-derived Huntington’s disease neurons.” Science Translational Medicine (2025).
Dolgin E. “Genes offer new clues to stopping Huntington’s disease in its tracks.” Science News, July 2026. https://www.sciencenews.org/article/genes-huntingtons-therapy-expansion