Diagnosis and therapy of Niemann-Pick disease type C1- what have we learned that can help veterinary patients?

Abstract

Naturally occurring hereditary diseases in dogs and cats can overcome major barriers in developing therapies for rare human genetic disorders, including limited natural history data, poor genotype-phenotype resolution, inadequate biomarkers, and weak translation from rodent models. By focusing on Niemann-Pick disease type C1 (NPC disease) in cats as a representative lysosomal disorder, the relevance of translating findings from large animal models to both pediatric medicine and veterinary neurology is discussed. The feline model of NPC disease closely mirrors the human disease genetically, biochemically, pathologically, and clinically, showing progressive cerebellar ataxia, Purkinje neuron loss, neuroaxonal dystrophy, hepatic disease, and abnormal cholesterol and sphingolipid storage. Studies in affected cats established the disease’s natural history, identified plasma 24(S)-hydroxycholesterol and spinal fluid calbindin D as biomarkers of disease progression, and enabled rigorous testing of therapies. Oral miglustat modestly delayed neurological decline, while intrathecal 2-hydroxypropyl-beta-cyclodextrin produced marked preservation of neurological function, prolonged survival, and reduced neuropathology, although ototoxicity emerged as an important adverse effect. These feline preclinical studies directly informed human clinical trial design, dosing, safety monitoring, and biomarker development, thereby accelerating therapeutic translation for children with NPC disease. Experimental Adeno-associated viral (AAV)-mediated gene therapy in cats is ongoing although current technical limitations of gene delivery for diffuse neurodegenerative disorders may limit efficacy. For veterinary clinical practice, the work supports improved and early diagnosis, breeding management, and the development of future treatment of feline NPC disease and other hereditary ataxias.

Keywords

Lysosomal storage disease / ataxia / animal model / Niemann-Pick disease type C / Purkinje neuron / cyclodextrin / veterinary

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