The overall objective of this project is for the Referral Center for Animal Models of Human
Genetic Disease (RCAM) to continue to serve as a national referral and resource center to
discover, characterize, and maintain colonies of large animals with hereditary diseases
homologous to those found in human patients that can be used to translate preclinical trials from
kennel to clinic. The naturally occurring animal models to be sought, and those currently
available, represent true orthologs of their respective human disease, involving defects in the
same genes and resulting in the same molecular, biochemical, pathological, and clinical signs
as in human patients. While numerous naturally occurring models of disease have been
identified and proven critical for preclinical trials, the rate at which new mutations are found and
characterized is limited. Therefore, we will now also create feline models that bear the same
genetic mutation as those found in human diseases using CRISPR/Cas9 genome editing.
These animal models can be generated quickly, will be completely orthologous to the human
system, and will be maintained in breeding colonies and disseminated to other investigators.
Both newly discovered and generated models are invaluable for the study of disease
pathogenesis and the evaluation of the safety and efficacy of therapies prior to clinical trials in
human patients. Models offering new opportunities to investigate disease pathogenesis and
approaches to therapy will be emphasized in consultation with an Advisory Committee. Verified
models will be made available to other investigators at a nominal fee-for-service in the form of
DNA, cells, frozen semen, and breeding stock. We will also serve as a resource for normal large
animals and their tissues for other investigators, and we will continue to offer facilities where
outside investigators can perform experiments in large animal models on a Program Income
Fund, fee-for-service basis.