Contact Information: Email: firstname.lastname@example.org; Phone: 607-253-4446
Sponsor: Collaborative Research Grants Program
Grant Number: N/A
Title: Canine Model of Centronuclear Myopathy for Gene and Stem Cell Therapy
Annual Direct Cost: $20,000
Project Period: 10/01/10-09/30/11
DESCRIPTION (provided by applicant): Human centronuclear myopathy (CNM) is a devastating inherited congenital myopathy with limited treatment options and no cure. Clinical signs range from generalized muscular weakness, atrophy, and hypotonia to ventilator-dependence and perinatal death.1 Gene and stem cell therapies offer promise for treating and potentially curing this disease, but intermediate (i.e., non-rodent) animal models are needed to develop and test these treatments. Canine CNM mimics the clinical and pathologic characteristics of its human counterpart and therefore offers an invaluable spontaneous model of disease with which to develop gene and stem cell therapies for human CNM. In Labrador Retrievers, CNM is inherited as an autosomal recessive trait with full penetrance.2 In affected dogs a short interspersed nuclear element (SINE) insertion present within exon 2 of the protein tyrosine phosphatase-like member A (PTPLA) gene leads to low-efficiency production of wild-type transcripts. This gene has been mapped to canine chromosome 2, a region orthologous to human chromosome 10p.3 Clinically apparent disease, including generalized weakness, exercise intolerance, atrophy, and abnormal spinal reflexes, is only present in homozygous mutant dogs. A subclinical form of CNM has been described, involving histopathologic abnormalities alone, although genotyping was not reported in these dogs.2 We propose establishing a canine model of CNM with which to ultimately investigate gene and stem cell therapies, as a pre-clinical model of human CNM. Our long-term hypothesis is that gene therapy and stem cell therapy can be used to treat CNM in dogs and that this treatment can be adapted for human use. Prior to therapeutic trials, however, we must establish a disease model and characterize measures of disease severity that are reliable, repeatable and multimodal. An initial cohort study will identify these measures. Our short-term hypothesis is that physical examination, electromyography, imaging, histopathology, and biomechanical and biochemical testing will provide reliable, objective measures of disease severity in affected (homozygous mutant) dogs, that can be used to evaluate treatment efficacy in subsequent therapeutic trials.