Developing therapies for cats, dogs & patients

© Easton Chen

There are no satisfactory therapies for many debilitating genetic neurological disorders. In the case of rare diseases, due to the small number of patients, even the natural course of the disease cannot be well understood. Naturally occurring hereditary diseases in cats and dogs are useful models for understanding disease progression and developing effective and safe therapies for diseases of the nervous system. Together, veterinarians, doctors and researchers are ready to develop therapies for diseases that were incurable in the past (1,2).

The development of effective therapies for many debilitating neurogenic diseases in patients is driven by 1) the relatively low incidence and high heterogeneity of these diseases, 2) an inadequate understanding of how the genetic defect leads to the phenotypic abnormalities, 3) the lack of validated surrogate markers that can be monitored as secondary clinical endpoints; and 4) the lack of available and potential therapies that substantially improve the disease in animal models.

Small and large animal models

Mouse models have been critical to the development of successful therapies. The ability to study both naturally occurring and man-made diseases in mouse models has led to the development of many therapies over the past 50 years that have positively impacted patient care. However, mouse models have limitations because of their low genetic diversity and because of their small size and short lifespan.

Large animal models serve as important intermediates in the evaluation of therapeutic strategies by 1) enabling natural history studies with large groups of animals with identical disease-causing mutations on a genetic background that is more diverse than in inbred rodents but less varied than in human patients; 2) assess disease progression and therapy safety using the same equipment (MRI, CT, PET, electrodiagnostic equipment) used in pediatric and general human patient populations; 3) repeated sampling of fluids and tissues; 4) accurate biodistribution studies due to increased brain and body size; and 5) long term efficacy and safety studies due to their extended lifespan. Although non-human primate, sheep, and swine models share some of these traits, naturally occurring diseases in non-human primates are rarely identified, and the extensive behavioral, clinicopathological, physiological, and anatomical knowledge available in dogs and cats far exceeds what is available in sheep and pigs.

Disease phenotyping

Neurological diseases are characterized by the enormous expertise of international veterinarians (often specialized veterinary neurologists) and state-of-the-art veterinary facilities. The examinations available in many specialized veterinary clinics include both routine and specialized physical, laboratory, radiological, ultrasound, magnetic resonance, and electrodiagnostic procedures. In addition to neurology, the specialties of veterinary medicine include anesthesia, behavior, ophthalmology, pediatrics, genetics, reproduction, endocrinology, cardiology, dermatology, internal medicine, pathology, nephrology, oncology, hematology, radiology, clinical pathology, immunology, nutrition, and soft tissue and orthopedic Surgery. Veterinarians on naturally occurring diseases in dogs and cats have been invaluable in educating the natural history and pathogenic mechanisms of neurological diseases.

Prevention of Disease in Animal Populations

Founded in 1974 at the University of Pennsylvania, the Referral Center for Animal Models of Human Genetic Disease (RCAM) is a unique resource dedicated to discovering and characterizing genetic diseases in animal patients. The RCAM identifies naturally occurring genetic diseases through 1) clinics at the University of Pennsylvania School of Veterinary Medicine; 2) tissue samples submitted to the Metabolic and Molecular Laboratory; or 3) Cooperations with an international network of veterinary specialists, researchers and institutions. Once the mutation responsible for the disease is identified, the next step is to develop tests for carrier and affected animals and recommend an informed breeding program to remove the disease from the animal population and preserve the gene pool.

Development of therapies for hereditary neurological diseases

Finally, naturally occurring diseases in dogs and cats have been critical in evaluating the long-term safety and effectiveness of new therapies. In many cases, animal clinical studies can be conducted with informed consent owned by customers. In rare diseases, however, breeding colonies can be established to better understand the course of the disease, develop biochemical and imaging biomarkers for the severity and course of the disease, and to study the safety and effectiveness of new therapies. These studies were directly responsible for introducing novel small molecule therapies, enzyme replacement therapies, and gene therapies into clinical trials in patients to improve human and animal health. An example of the usefulness of these naturally occurring diseases are studies of the Niemann-Pick Disease Cat C1 (NPC1), which provided critical information about the route of administration, dose scaling and side effects of a small molecule, and the development of surrogate biomarkers of therapeutic efficacy that would not have been possible with the mouse model (3). These studies in the cat model accelerated the transfer of this small molecule to children in the NPC1 mouse model, resulting in a multinational phase 3 clinical trial of clinical efficacy (4).

A second example includes the development of AAV-mediated gene therapy administered at the magna cistern to treat previously untreatable globoid cell leukodystrophy (Krabbe’s disease) in dogs (5); this therapy is now being developed for use in infants. Similar preclinical studies in large animal models of mucopolysaccharidosis and idiopathic epilepsy have led to planned or ongoing clinical trials in patients.

The future

Together, veterinarians, physicians and researchers open new doors to understanding neurological diseases and developing new therapies. By collaborating on diseases that affect many species, cures for neurological diseases are developed that will benefit both veterinary and human patients.


  1. Gurda BL, Bradbury AM, Vite CH. Dog and cat models of human genetic diseases and their contribution to the further development of clinical therapies. Yale J. Biol. Med. 90: 417-431, 2017. PMC5612185.
  2. Gurda BL, Vite CH. Large animal models help develop therapies for central and peripheral nervous system dysfunction in patients with lysosomal storage disease. Hum Mol Genet 28: R119-R131, 2019.
  3. Vite CH, Bagel JH, Swain GP, ​​Prociuk M, Sikora TU, Stein VM, O’Donnell P, Ruane T, Ward S, Crooks A, Li S, Mauldin E, Stellar S, De Meulder M, Kao ML, Ory DS, Davidson C, Vanier MT, Walkley SU. Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick disease type C1. Sci Transl Med 7 (276): 276ra26. doi: 10.1126 / scitranslmed.3010101, 2015. PMC4415615.
  4. Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao K, Silver SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxy-beta-cyclodextrin decreases neurological disease progression in Niemann-Pick disease type C1: an ad hoc analysis of a non-randomized, open-label phase 1/2 study. Lancet August 10 pii: S0140-6736 (17) 31465-4. doi: 10.1016 / S0140-6736 (17) 31465-4, 2017. PMC6176479.
  5. Bradbury AM, Bagel JH, Nguyen D, Lykken E, Pesayco-Salvador J, Jiang X, Swain GP, ​​Hendricks IJ, Miyadera K, Hess RS, Ostrager A, ODonnell P, Sands MS, Ory DS, Shelton GD, Bongarzone ER, Gray SJ, Vite CH. Krabbe disease successfully treated by monotherapy of intrathecal gene therapy. J Clin Invest Volume 130, Issue 9 (September 1, 2020). PMC7456224.

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