In a paper published in Cell, an international team of researchers developed a knock-in pig model of Huntington's disease that recapitulates neurological and respiratory symptoms of the disease in humans.
Huntington's disease is caused by protein misfolding of mutant Huntington (HTT) due to large numbers of CAG trinucleotide repeats in the gene. Longer repeats correlate with earlier disease onset and increased disease severity.
Animal models that accurately model human disease are lacking. Transgenic mouse models do not develop the respiratory symptoms associated with Huntington's disease, and knock-in mouse models do not develop neurodegeneration to the extent seen in human patients.
In previous studies, transgenic pig models did not develop neurodegenerative symptoms or tended to die soon after birth.
In the Cell study, researchers from Emory University School of Medicine, Jinan University and Chinese Academy of Sciences generated a knock-in pig model of Huntington's disease by using CRISPR-Cas9 gene editing to knock in 150 consecutive CAG repeats into the endogenous HTT gene in pig fibroblast cells, creating a disease variant that represents a "full-length" mutant HTT. Somatic cell nuclear transfer (SCNT) from cells with correctly edited HTT into oocytes created pig embryos, which were transferred into surrogates.
Brains from the Huntington's disease pigs had increased neuronal degeneration and demyelination and mutant HTT aggregation than brains from pigs with normal HTT expression. Additionally, the pig's brains were smaller and had fewer neurons in the striatum. Degeneration of neurons in the stratium in the pig model was similar to neuronal degeneration in the same region in Huntington's disease patients.
The knock-in Huntington's disease pigs had reduced mobility, respiratory function, weight gain and survival compared with age- and sex-matched pigs with normal HTT expression.
In the paper, the authors suggest larger animal models like pigs can better model neurodegenerative diseases including Alzheimer's and Parkinson's disease than smaller rodent models.