What is Huntington's Disease?
 

Huntington's Disease (HD) is a rare neurodegenerative disorder primarily characterized by progressively worsening choreiform movements, psychiatric disturbances, and cognitive decline. The disease is inherited in an autosomal dominant pattern. Its pathological hallmark is neuronal degeneration in the caudate nucleus, other deep brain nuclei, and the cerebral cortex, leading to striatal atrophy. The incidence of HD varies significantly by region, being higher in Europe (5.65 per 100,000) and North America (7.43 per 100,000) compared to Asia (0.99 per 100,000). The typical age of onset is between 35 and 50 years, with an average survival period of approximately 10 to 20 years after diagnosis.
 

Pathogenesis
 

Huntington's Disease is caused by a dominant mutation in the first exon of the Huntingtin gene (HTT) located on chromosome 4. The mutation involves an abnormal expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeat sequence to more than 35 repeats. This expansion results in an abnormally long polyglutamine (polyQ) chain in the encoded mutant huntingtin protein (mHTT). The mHTT accumulates abnormally within neurons, forming intranuclear and cytoplasmic inclusions that interfere with cellular function, ultimately leading to neuronal death. Research has shown a correlation between the number of CAG repeats, age of onset, and disease severity, with higher repeat numbers associated with earlier onset and more severe progression.

 

(Image: PubMed)

Gene Therapy
 

● Antisense Oligonucleotide (ASO) Therapy: Designed to specifically bind to mRNA, preventing the synthesis of the mutant huntingtin protein (mHTT). Recent research has found that the DNA mismatch repair protein MSH3 drives somatic CAG repeat expansion. ASOs targeting MSH3 have been shown to effectively reduce CAG repeat expansion in induced pluripotent stem cell (iPSC)-derived striatal neurons with a favorable safety profile.

● Gene Editing Technology: Aims to directly edit and correct the mutated HTT gene. A research team from the Jinan University's Guangdong-Hong Kong-Macao Institute of CNS Regeneration successfully applied a gene editing system to a large animal model (pig model) of HD, achieving highly efficient knockdown of HTT mRNA. In a Huntington's Disease 140Q-KI mouse model, this technology alleviated gliosis and improved motor dysfunction.

● Advanced Delivery Systems: A research team led by Professor Cai Yujia at Shanghai Jiao Tong University, in collaboration with Fudan University and AstraZeneca, developed a novel gene editing delivery tool named RIDE (Ribonucleoprotein delivery). This technology utilizes virus-like particles (VLPs) to deliver CRISPR-Cas9 ribonucleoprotein (RNP), achieving neuron-specific gene editing. In an HD mouse model, knocking out the CAG repeat sequences significantly reduced mutant huntingtin protein expression and improved disease symptoms.

(Image: PubMed)

● RNA Interference (RNAi) Technology: RNAi utilizes small interfering RNA (siRNA) or short hairpin RNA (shRNA) to specifically degrade target mRNA. Artificially engineered miRNAs can specifically target HTT mRNA. In a transgenic sheep model, an engineered miRNA significantly reduced the levels of human mutant huntingtin protein throughout the striatum.

Mouse Models

● HTT N-terminal Fragment Models: Express a small portion of the human HTT gene from the 5' end, including exon 1 containing the CAG repeat region.

○ R6/1 Mice: Contain 115 CAG repeats. They exhibit slower onset, with neurological symptoms appearing at 22-26 weeks, reaching end-stage at 38-40 weeks. Main features include motor deficits, weight loss, and striatal degeneration.

○ R6/2 Mice: Contain approximately 145 CAG repeats. They exhibit early and rapid disease progression, with motor dysfunction, weight loss, and reduced striatal volume evident at 5-6 weeks, reaching end-stage at 12-14 weeks. One of the most widely used models.

● Full-Length HTT Models: Express the full-length human mutant HTT protein via yeast or bacterial artificial chromosomes (YAC or BAC).

○ YAC128 Mice: Contain 128 CAG repeats. They exhibit hyperactivity at 3 months, followed by motor deficits, and hypokinesia by 12 months, modeling slowly progressing HD.

○ BACHD Mice: Contain 97 mixed CAA-CAG repeats. They exhibit progressive motor deficits, neuronal synaptic dysfunction, and striatal atrophy, suitable for preclinical studies.

○ BAC226Q Mice: Carry 226 mixed CAG-CAA repeats and contain the endogenous human HTT promoter and regulatory elements. They exhibit motor deficits, striatal atrophy, neuronal loss, and a shortened lifespan. Symptoms are more accurate and onset earlier compared to BACHD mice. Motor deficits include sudden head and body twitches and contortions, resembling the choreiform movements of HD patients.

● Knock-in Models: Replace the mouse Htt gene exon 1 with the human HTT CAG repeat sequence.

○ zQ175 Mice: Derived from a spontaneous expansion of CAG repeats in the CAG140 mouse model. They develop motor deficits and weight loss at 2-4 months, and striatum-dependent cognitive deficits at 10-12 months.

○ HdhQ150 Mice: Begin to show significant motor deficits and weight loss around 70 weeks, with reduced striatal neuron numbers evident by 100 weeks. Their long timescale of neuronal decline makes them useful for studying early mechanisms of HD neurodegeneration.

○ CAG140 Mice: Contain 140 CAG repeats. They exhibit increased activity at 4-5 weeks, followed by reduced activity at 18-20 weeks, gait abnormalities at 1 year, and impaired long-term recognition memory. The olfactory system shows clear abnormalities early in the disease course.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various HD mouse models according to client needs, such as R6/1 mice, R6/2 mice, YAC128 mice, BACHD mice, BAC226Q mice, zQ175 mice, HdhQ150 mice, and CAG140 mice. We welcome inquiries!
 

References:

[1] Kozłowska E, Ciołak A, Adamek G, Szcześniak J, Fiszer A. HTT loss-of-function contributes to RNA deregulation in developing Huntington's disease neurons. Cell Biosci. 2025 Jul 9;15(1):100. doi: 10.1186/s13578-025-01443-5. PMID: 40635054; PMCID: PMC12239503.

[2] Bunting EL, Donaldson J, Cumming SA, Olive J, Broom E, Miclăuș M, Hamilton J, Tegtmeyer M, Zhao HT, Brenton J, Lee WS, Handsaker RE, Li S, Ford B, Ryten M, McCarroll SA, Kordasiewicz HB, Monckton DG, Balmus G, Flower M, Tabrizi SJ. Antisense oligonucleotide-mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington's disease iPSC-derived striatal neurons. Sci Transl Med. 2025 Feb 12;17(785):eadn4600. doi: 10.1126/scitranslmed.adn4600. PMID: 39937881.

[3] Ling S, Zhang X, Dai Y, Jiang Z, Zhou X, Lu S, Qian X, Liu J, Selfjord N, Satir TM, Lundin A, Touza JL, Firth M, Van Zuydam N, Bilican B, Akcakaya P, Hong J, Cai Y. Customizable virus-like particles deliver CRISPR-Cas9 ribonucleoprotein for effective ocular neovascular and Huntington's disease gene therapy. Nat Nanotechnol. 2025 Apr;20(4):543-553. doi: 10.1038/s41565-024-01851-7. PMID: 39930103; PMCID: PMC12015117.

[4] Fu Shuo, Zhang Wen, Song Junke, et al. Research Progress on Experimental Animal Models of Huntington's Disease. Acta Laboratorium Animalis Scientia Sinica, 2024, 32(8): 1065-1076.

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