Huntington's disease (HD) is an autosomal dominant neurodegenerative disease for which there is currently no available cure. Before cell therapies can be introduced into the clinic, efficacy must first be shown in animal models of the disease. Although excellent murine models of HD exist, efficacy testing of human stem cell products in transgenic mouse models is challenged by a xenogeneic immune response in the animal which causes rejection of the human cells. We have developed two immune deficient and xeno-tolerant mouse models of Huntington's disease to allow efficacy testing of human cell-based therapies Our hypothesis is that our novel YAC128/NSG and R6/NSG strains that we are characterizing will provide xeno-tolerant Huntington's disease mouse models capable of retaining human stem cell products while displaying phenotypic disease progression for efficacy testing of proposed therapies. Huntington's disease transgenic mouse strains that lack an immune system could provide a powerful model for proof of efficacy testing of candidate human adult and pluripotent cell therapies for HD patients. The mice have been generated and we are now poised for further testing and characterization, plus expansion for distribution. Both strains of mice have the characteristic aggregates in their brain tissue. The normally very short-lived R6 strain has a significantly prolonged lifespan, in the absence of an immune system, further implicating the role of the immune system in disease progression.
In Aim 1 we will continue to expand and fully characterize the two new strains of mice.
In Aim 2 we will assess permissiveness for human stem/progenitor cell retention in the brain.
In Aim 3 we will determine whether the immune deficient HD mice have the presence of the well characterized HD phenotypes observed in the parental strains, using behavioral and phenotypic assays established in our laboratory.
In Aim 4 we will humanize R6/2/NSG and YAC128/NSG pups at birth to create relevant models to study the human immune system response to anti-Htt therapies in the pipeline to treat HD and Juvenile HD. The humanization of these strains could provide valuable insight into the role of the human immune system in HD progression, and will be useful models in which to perform anti- htt drug, viral vector, gene editing, and antibody testing.
We are developing two immune deficient, xeno-tolerant mouse models of Huntington's disease to allow engraftment of human cells without the need for potentially toxic immune suppressants. These novel strains could provide powerful models for efficacy testing of candidate human adult and pluripotent cell therapies for HD patients. Humanization of these strains could provide valuable insight into the role of the human immune system in HD progression.