PHILADELPHIA, PA — Latus Bio Inc. has published research supporting a gene therapy approach that could slow Huntington’s disease progression by targeting a DNA repair protein linked to neuronal damage, providing a computational and preclinical foundation for its experimental treatment, LTS-201.
The peer-reviewed study, published in Nature Communications, combines human disease progression data, computational modeling and animal experiments to examine whether reducing the protein MSH3 could delay symptoms and preserve neurological function.
The findings support a therapeutic strategy aimed at somatic instability, a process in which inherited DNA repeat sequences expand within cells over time. That expansion is increasingly implicated in the onset and progression of Huntington’s disease, an inherited neurological disorder that progressively impairs movement, cognition and behavior.
Unlike approaches focused primarily on the huntingtin protein associated with the disease, Latus Bio’s strategy targets a DNA repair mechanism that contributes to the continued expansion of the genetic mutation within vulnerable neurons.
The company’s investigational treatment, LTS-201, uses an engineered adeno-associated virus, or AAV, to deliver an artificial microRNA designed to reduce MSH3 expression in specific brain cells.
The therapy incorporates AAV-DB-3, a viral delivery system engineered to target medium spiny neurons in the striatum and projection neurons in the cerebral cortex. Medium spiny neurons are particularly vulnerable to degeneration in Huntington’s disease.
In nonhuman primates, LTS-201 reduced MSH3 messenger RNA levels by 48% to 94%, depending on the dose, in more than 90% of medium spiny neurons examined.
Separate experiments in a mouse model of Huntington’s disease demonstrated dose-dependent reductions in somatic instability within the striatum, providing evidence that lowering MSH3 can affect the underlying DNA expansion process.
The research also introduced a computational model built using human natural history data and measurements of somatic expansion in human neurons.
The model estimates how different levels of MSH3 suppression could influence disease progression across patients with varying inherited CAG-repeat lengths and at different ages of treatment.
Simulations suggested that substantial, sustained reductions in MSH3 could delay motor symptom onset and slow clinical deterioration by years, with earlier intervention potentially producing benefits measured in decades.
The model also predicted that deeper suppression of MSH3 in a smaller proportion of vulnerable neurons could produce greater therapeutic benefits than weaker suppression across a larger population of cells.
That finding could influence gene therapy development by establishing quantitative targets for the degree of MSH3 reduction needed to produce a meaningful clinical effect.
The researchers modeled changes in the composite Unified Huntington’s Disease Rating Scale, or cUHDRS, a measure used to assess disease progression. Their simulations predicted changes in the rate of clinical decline ranging from approximately 50% to more than 120% relative to natural history.
Those estimates are computational predictions rather than demonstrated clinical outcomes. The experimental findings establish target engagement and effects on somatic instability in animal models, not evidence that LTS-201 slows Huntington’s disease in patients.
“Genetic studies increasingly point to somatic instability as the central driver of Huntington’s disease progression,” said Jang-Ho J. Cha, chief science and medical officer of Latus Bio and a co-corresponding author of the study.
“This work establishes a translational framework that quantitatively links MSH3 lowering to reductions in somatic instability and to years of predicted clinical benefit in HD,” Cha said.
The study was co-led by Beverly L. Davidson, chair of Latus Bio’s scientific advisory board, and builds on previously published research describing the AAV-DB-3 delivery technology.
Davidson said the findings demonstrate how computational modeling can be combined with gene therapy engineering to guide the development of treatments intended to alter disease progression.
The researchers also identified potential applications for the modeling framework in other disorders involving unstable DNA repeat expansions, including X-linked dystonia-parkinsonism and myotonic dystrophy type 1.
For Latus Bio, the publication provides additional preclinical evidence supporting LTS-201 and a quantitative framework for evaluating the level of MSH3 suppression that may be necessary to achieve therapeutic effects.
The research, titled “Computational modeling and preclinical evaluation support targeting somatic instability for Huntington’s disease treatment,” appears in Nature Communications.
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