University or Institution

University of Pennsylvania

Area of Research:

The RCAM goals are:

  1. To identify hereditary metabolic diseases within the dog and cat population,
  2. To develop precise diagnostic tests for carriers and affected animals,
  3. To recommend informed breeding of carrier and normal animals to preserve gene pools,
  4. To maintain colonies of hereditary disorders in dogs and cats to better understand disease pathogenesis and to develop therapies, and
  5. To provide tissues samples and large animal models of human genetic disease to investigators in order to better understand disease pathogenesis and as preclinical models for potential human clinical trials.

Primary Mentor:

Charles H Vite, DVM, PhD, Dipl ACVIM (Neurology), Professor of Neurology, [email protected]; Director of RCAM (https://www.vet.upenn.edu/research/core-resources-facilities/referral-center-for-animal- models)

Mentor Team:

John H. Wolfe, VMD, PhD, Professor of Pathology and Medical Genetics

Margret Casal, Dr. Med Vet, PhD, Professor of Medical Genetics Paula Henthorn, PhD, Professor of Medical Genetics

Description of Potential Research Project(s):

In the past five years, in collaboration with the office of Therapeutics for Rare and Neglected Diseases at NIH, the Niemann Pick disease type C1 (NPC1) cat model accelerated the translation of a promising experimental therapy in the NPC1 mouse model to children by providing critical information on route of delivery, scaling of dose, adverse events, and surrogate biomarkers that would not have been feasible using the mouse model. Notably, this work led to the development of a phase 1/2a trial of 2-hydroxypropyl-beta-cyclodextrin that has yielded promising efficacy data and supported the initiation of a multinational phase 2b/3 clinical efficacy trial that has been approved by both the FDA and EMA. In collaboration with Edimer Pharmaceuticals, neonatal dogs with X-linked ectodermal dysplasia (XLHED) received the recombinant protein EDA200, which improved the development of sweat glands, teeth, tear production and pulmonary function that is normally compromised in these dogs. The results of these experiments were submitted to the FDA and supported the first clinical trials of children with XLHED. In a U01 collaborative project with the NIH Magnuson Clinical Center, the feline alpha- mannosidosis model was used to evaluate CSF directed delivery of adeno-associated viral vectors to treat the brain to support development of an IND for a first-in-human gene therapy trial using a CSF delivery route for AAV in alpha-mannosidosis. Similar preclinical trials in large animal models of the mucopolysaccharidoses, globoid cell leukodystrophy, hemophilia, cystinuria, and epilepsy have resulted in planned or ongoing clinical trials in patients. The fellow will focus on a disease model within their specialty (neurology, internal medicine, cardiology, clinical pathology, dermatology)

Additional Training Opportunities:

The University of Pennsylvania is well equipped to support translational research. The majority of the project will be conducted at the School of Veterinary Medicine, however, resources available at the Perelman School of Medicine will also be utilized. The expertise and resources for translational research are unparalleled, with numerous centers including the Smilow Center for Translational Research, Institute for Translational Medicine and Therapeutics, and the Clinical and Translational Research Center. Research on rare diseases is heightened by the innovative Center for Orphan Disease Research and Therapy, which has research facilities dedicated to discovering and translating therapies. Collaborations between the school of veterinary medicine and school of medicine are encouraged and supported through regular conferences and symposia.

The fellow will be expected to attend weekly seminars at the Institute for Translational Medicine and Therapeutics, the Mahoney Institute of Neurological Sciences, and the Center for Neurodegenerative Disease Research. In addition to the aforementioned University of Pennsylvania facilities, the Wistar Institute and Children’s Hospital of Philadelphia (CHOP) are located on campus and work in close collaboration with the university.

Dr. Vite and Dr. Wolfe are skilled in grant writing. They will devote time monthly to training in grant writing and the fellow will also be expected to assist in the submission of two grants currently in preparation.

The fellow will be expected attend/present at weekly lab meetings, and to present data yearly at the ACVIM symposia and at the American Society of Gene and Cell Therapy.

Contact Information for Interested Potential Trainees:

Charles H Vite, DVM, PhD, Dipl ACVIM (Neurology), Professor of Neurology, [email protected]; Director of RCAM (https://www.vet.upenn.edu/research/core-resources-facilities/referral-center-for-animal- models)