Modeling the genomic instability of Huntington’s Disease with iPSC technology
Summary
Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric decline. The hallmark of HD pathophysiology is the selective loss of neurons in the striatum.
HD is caused by the expansion of a CAG trinucleotide repeat in the HTT gene, leading to the production of mutant huntingtin (mHTT), a protein with toxic gain-of-function properties. CAG repeat length influences disease onset and progression, with longer repeats linked to more severe phenotypes. The region is somatically unstable and expands over time, making the detection and monitoring of CAG expansion critical for understanding disease variability and evaluating new therapies.
There are currently no FDA-approved therapies that halt or reverse HD progression. Therapeutic development has focused on symptomatic management, however recent advances in genetic targeting and small-molecule discovery offer potential for disease-modifying interventions.
Drug discovery researchers utilize both animal (in vivo) and cell culture (in vitro) models to study HD. In vivo models primarily help evaluate therapeutic efficacy and systemic effects, while in vitro models enable human-specific investigations such as customized disease models and identification of potential therapeutics that may alter disease progression.
Human induced pluripotent stem cell (iPSC)-derived models are showing promise as a scalable and physiologically relevant platform for HD research. Importantly, these models retain the donor’s genetic background, CAG repeat mutations and can be differentiated into relevant cell populations including striatal neurons.
Axol Bioscience has developed iPSC lines from five HD patients and one asymptomatic carrier. One of these, the CENSOi019-B line (HTT: 14/127 CAG, now CAG143) contains an atypical allele that displays instability in culture and is associated with accelerated disease onset. Striatal neurons derived from this iPSC line provide a model for longitudinal studies of repeat expansion and neurodegeneration.
To replicate HD pathology in vitro, morphological and functional endpoints such as trinucleotide instability, neurite outgrowth and spontaneous firing can be assessed. These assays provide functional insights into HD progression and support evaluation of therapeutic candidates.
Here, we outline the development and characterization of iPSC-derived striatal neurons and their application in the modeling of Huntington’s Disease in vitro.