Allopregnanolone Therapy in Feline Niemann-Pick Type C
ACVIM 2008
Charles H. Vite1; Wenge Ding1;Caroline Bryan1;Patricia O'Donnell1;Karyn Cullen1;David Aleman1;Sergey Magnitsky2; Harish Poptani2;G. Diane Shelton3; Mark Haskins1;Tom van Winkle1; Synthia Mellon4;Steven Walkley5
1School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3School of Medicine, University of California, San Diego, La Jolla, CA, USA; 4University of California, San Francisco, CA, USA; 5Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

The only large animal model of Niemann-Pick type C (NP-C) disease is a colony of cats housed at the School of Veterinary Medicine of the University of Pennsylvania. The disease in cats, due to a point mutation in the NPC1 gene, is a homologue of the disease in children with similar clinical, biochemical, and neuropathologic abnormalities. We have extended the natural history study of feline NP-C disease progression and successfully used allopregnanolone to partially treat neurologic and hepatic components of the disease. Statistically significant differences between age-matched NP-C and normal cats were identified in measures of weight gain, onset of neurological dysfunction, post-rotatory nystagmus, nerve conduction velocity, brain stem auditory evoked response testing, liver enzyme concentrations, chitotriosidase activity, nuclear magnetic resonance measures of the brain's gray and white matter, and brain, liver, lung, and peripheral nerve histology. All these differences serve as markers of disease and demonstrate that the feline model has been developed to a point where it is a significant resource for evaluating experimental therapies of NP-C disease.

We have treated ten NP-C cats with allopregnanolone and have shown significant improvements in many of our measures of NP-C disease. Cats that began treatment with allopregnanolone after 3 weeks of age (AlloLate) showed significant improvements in tibial nerve conduction velocity, liver enzyme concentrations, chitotriosidase activity, and brain and liver pathology. However, there was no improvement in onset and severity of signs of neurologic dysfunction or in lifespan. A cohort of cats treated with allopregnanolone at 1, 3, 7, 14, and 21 days (AlloEarly) are currently being assessed to determine whether the earlier administration of allopregnanolone improves neurologic disease in an animal model other than mice. Data suggests that the early administration of allopregnanolone may delay the onset of neurological dysfunction in cats.

Our continuing goals are to use this well-characterized large animal model to assess the efficacy of experimental therapies of NP-C disease and to better understand NP-C disease pathophysiology.

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Charles Vite

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