Huntington’s Disease (HD) is a rare neurodegenerative disorder characterized by progressive chorea, psychiatric disturbances, and cognitive decline. It is inherited in an autosomal dominant manner, with pathological features including neuronal degeneration in the caudate nucleus, other deep brain nuclei, and the cerebral cortex, leading to striatal atrophy.
Prevalence varies significantly across regions: higher in Europe (5.65/100,000) and North America (7.43/100,000) than in Asia (0.99/100,000). Onset typically occurs between ages 35–50, with an average survival of 10–20 years.
Pathogenesis
HD is caused by a dominant mutation in the first exon of the huntingtin gene (HTT) on chromosome 4. The mutation involves expansion of a CAG trinucleotide repeat beyond 35 copies, resulting in an abnormally long polyglutamine (polyQ) tract in the mutant huntingtin protein (mHTT).
mHTT accumulates abnormally in neurons, forming inclusion bodies that disrupt cellular function and ultimately cause neuronal death. Longer CAG repeats correlate with earlier onset and more severe disease.
Gene Therapy
Antisense Oligonucleotide (ASO) Therapy
ASOs specifically bind to mRNA and block synthesis of mHTT. Recent studies show that the DNA mismatch repair protein MSH3 drives somatic CAG repeat expansion. MSH3-targeting ASOs effectively reduce CAG expansion in iPSC-derived striatal neurons with good safety profiles.
Gene Editing
Gene editing directly repairs the mutant HTT gene. A team at Jinan University’s Guangdong-Hong Kong-Macao Institute of CNS Regeneration first applied gene editing to a large-animal (porcine) HD model, achieving efficient HTT mRNA knockdown. In 140Q-KI HD mice, the technology reduced gliosis and improved motor function.
Additionally, Dr. Yujia Cai’s team at Shanghai Jiao Tong University, together with Fudan University and AstraZeneca, developed RIDE (Ribonucleoprotein Delivery), a novel gene-editing delivery platform. Using virus-like particles (VLPs) to deliver CRISPR-Cas9 ribonucleoproteins (RNPs), it enables neuron-specific gene editing. In HD mice, deletion of the CAG repeat significantly reduced mHTT expression and improved symptoms.
RNA Interference (RNAi)
RNAi uses siRNA/shRNA to degrade target mRNA. Engineered miRNAs specifically target HTT mRNA. In transgenic sheep, artificial miRNAs substantially reduced human mHTT levels throughout the striatum.
Mouse Models
1. HTT N-terminal editing models
Carry a portion of the human HTT 5’ end, including exon 1 with the CAG repeat.
- R6/1 mice: 115 CAG repeats; slow onset, neurological symptoms at 22–26 weeks, end-stage at 38–40 weeks. Phenotypes: motor impairment, weight loss, striatal degeneration.
- R6/2 mice: 145 CAG repeats; early, rapid progression. Motor dysfunction at 5–6 weeks, end-stage at 12–14 weeks. One of the most widely used HD models.
2. Full-length HTT transgenic models (YAC/BAC)
Express full-length mutant human HTT via yeast/bacterial artificial chromosomes.
- YAC128 mice: 128 CAG repeats; hyperactivity at 3 months, progressive motor impairment, hypokinesia at 12 months. Mimics slowly progressive HD.
- BACHD mice: 97 mixed CAA-CAG repeats; progressive motor deficits, synaptic dysfunction, striatal atrophy. Ideal for preclinical studies.
- BAC226Q mice: 226 mixed CAG-CAA repeats with endogenous human HTT promoter/regulatory elements. Severe motor deficits, striatal atrophy, shortened lifespan. Earlier onset and more accurate phenotypes than BACHD, with choreiform-like jerking/twisting.
3. Knock-in models
Mouse Htt exon 1 replaced with human HTT CAG repeats.
- zQ175 mice: Derived from spontaneous CAG expansion in CAG140 mice. Motor impairment/weight loss at 2–4 months, striatum-dependent cognitive deficits at 10–12 months.
- HdhQ150 mice: Overt motor impairment/weight loss at 70 weeks, reduced striatal neurons at 100 weeks. Long neuronal decline phase; useful for studying early neurodegeneration.
- CAG140 mice: 140 CAG repeats; hyperactivity at 4–5 weeks, hypoactivity at 18–20 weeks, gait abnormalities at 1 year. Impaired long-term recognition memory and early olfactory dysfunction.
MingCeler Bio Supports HD Gene Therapy Research
Gene therapy brings hope for rare diseases, yet its development and validation rely heavily on animal models. Leveraging our proprietary TurboMice™ technology, MingCeler Bio has developed multiple rare disease mouse models.
TurboMice™ overcomes long modeling cycles and low success rates for complex models. It enables editing at nearly any target gene locus, generating fully homozygous gene-edited mice directly from ES cells in as little as 2 months.
MingCeler Bio can customize a wide range of HD model mice, including R6/1, R6/2, YAC128, BACHD, BAC226Q, zQ175, HdhQ150, CAG140, and more.
Contact us for your HD research needs!