In Vivo Models for Translation of Huntington’s Disease in Humans

We conduct contract in vivo Huntington’s disease animal studies to test the efficacy of novel therapeutics. We offer two mouse models, the Q175 mouse model, and the transgenic R6/2 mouse model, as well as rat and large animal studies. All of our studies display robust, gene dose-dependent, progressive, and early-onset alterations in the validated endpoint assays. As part of our Neuroscience and Rare Disease portfolio, we also offer a selection of validated in vitro Huntington disease assays as well.

Q175 Mouse Model

The Q175 knock-in mouse is one of our two Huntington’s disease animal models. The Q175 Mouse contains human mHTT allele with the expanded CAG repeat (~179 repeats) within the native mouse huntingtin gene. Thus, this animal model reflects an accurate representative of Huntington’s disease in humans from a genetic aspect. Both homo- and heterozygous Q175 mice exhibit first signs of motor symptoms early, from 3-4 months of age, and behavioral deficits are accompanied by marked brain atrophy and brain metabolite changes by eight months.

Dopamine Neuron

The Expanded Cag Repeat in the Huntingtin Gene as Target for Therapeutic Rna Modulation Throughout the Hd Mouse Brain

Research conducted by BioMarin BV and Charles River demonstrates the therapeutic capacity of an antisense oligonucleotide with the sequence (CUG)7 targeting the expanded CAG repeat in huntingtin (HTT) mRNA in vivo in the R6/2 N-terminal fragment and Q175 knock-in Huntington's disease (HD) mouse models.

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Transgenic R6/2 Mouse Model

Our most commonly used model is the transgenic R6/2 mouse model [B6CBA-Tg(HDexon1)62Gpb/1J]. The R6/2 mouse contains N-terminally truncated mutant HTT (mHTT) with CAG repeat expansion (~125 repeats) within the huntingtin gene exon 1. This model develops HD-like symptoms, including decreased body weight as well as motor and cognitive deficits, starting as early as 6-8 weeks of age. Survival is followed until 25 weeks of age.

Huntington’s disease animal model components:

  • Body weight
  • Motor deficits
    • Open field test
    • Rear climbing test
    • Rotarod test
    • Grip strength test
  • Cognitive deficits
    • Procedural two-choice swim test
    • Contextual fear conditioning
    • Neurological index
  • In vivo brain imaging
    • MRI for brain volumetry (whole brain, cortex, striatum)
    • MRS for striatal metabolites
  • Biomarkers
  • Various options in mRNA and protein detection assays

Additional Endpoints:

Several additional endpoints are available for evaluating the lead compound method of action, such as:

  • IHC for mutated Huntingtin protein
  • Inflammatory markers
  • Iron accumulation and dopaminergic neurotransmission for intensity analysis or stereological counting
  • qPCR assays for various transcripts

Choose Your Model

Stem Cell-Derived Striatal Neurons for In Vivo Huntington’s Disease Studies

Mariangela Iovino, PhD, Group Leader of Integrated Biology at Charles River presents at Neuroscience Day 2020 and takes a deep dive in to current Huntington’s disease research with stem cell-derived striatal neurons. View additional Neuroscience Day 2020 presentations here.

 

Frequently Asked Questions (FAQs) for Huntington’s Disease Animal Studies