Modeling the genomic instability of Huntington’s Disease with iPSC technology

This 2025 publication from Axol Bioscience presents a comprehensive overview of how iPSC-derived models are advancing Huntington’s Disease (HD) research. HD is a fatal neurodegenerative disorder caused by CAG repeat expansions in the HTT gene, leading to the production of mutant huntingtin protein (mHTT). Axol’s iPSC-derived striatal neurons provide a human-relevant platform to study disease mechanisms, progression, and therapeutic interventions.

Key highlights include:

• Axol’s HD iPSC Collection:
  • Five iPSC lines from HD patients and one asymptomatic carrier
  • Genotyped and validated for CAG repeat length, pluripotency, and karyotype
  • Differentiated into striatal neurons (ax2019), astrocytes, and microglia
• CAG Repeat Instability Modeling:
  • The CENSOi019-B line (HTT: 14/127 CAG, now CAG143) shows progressive CAG expansion in vitro
  • Enables longitudinal studies of somatic instability and early-onset HD
• Functional Assays and Endpoints:
  • Trinucleotide instability, neurite outgrowth, spontaneous firing
  • Additional endpoints: mitochondrial function, protein aggregation, phagocytosis
• CRISPR Gene Editing for Isogenic Controls:
  • Generation of isogenic lines with reduced CAG repeats (<36)
  • Facilitates controlled studies of CAG-length-dependent phenotypes
• Emerging Technologies:
  • Integration with transcriptomics, proteomics, and metabolomics
  • Use of organoid-on-chip and microfluidic platforms for real-time disease modeling
  • Co-culture systems with astrocytes and microglia to mimic brain microenvironments

These models are instrumental in understanding HD pathogenesis, identifying genetic modifiers like FAN1, and accelerating the development of targeted therapies. The CENSOi019-B line, in particular, offers a unique opportunity to study early-onset HD and CAG repeat dynamics in a controlled, scalable in vitro system.

Featured Axol Products:

• axoCells™ Striatal Neurons (ax2019) – Derived from HD patient iPSC lines, including CENSOi019-B
• Axol HD iPSC Collection – CENSOi019-B, CENSOi019-A, CENSOi052-A, CENSOi017-A, CENSOi011-D, CENSOi053-A