Recombinetics, Inc. — Department of Health and Human Services SBIR Phase I: 300

Description

DESCRIPTION provided by applicant Microvillus inclusion disease MVID is the most severe cause of Congenital Diarrheal Diseases in neonates MVID results from mutations that lead to malabsorption and life threatening intractable secretory diarrhea To date no curative therapy exists MVID patients are largely dependent on parenteral nutrition Prognosis is generally poor due to metabolic decompensation dehydration infections and liver complications associated with parenteral nutrition The only alternative therapy to parenteral nutrition is intestinal transplantation MVID accounts for of pediatric bowel transplantation worldwide However the overall five year survival after small bowel transplantation is only about Parenteral nutrition and bowel transplants are non permanent solutions for treating MVID further work in deciphering how inactivating mutations in MYO B lead to aberrant trafficking in enterocytes will provide novel insights into genotype phenotype relations and pave the way for development of improved diagnosis and viable alternative therapeutic strategies There is a limited availability of patient material and no suitable animal models for MVID hampering the thorough understanding of the diseaseandapos s molecular mechanisms While we have recently been able to develop a mouse model of germline and intestinally targeted deletion of MYO B these mice die in their first week of life so any analysis of interventions that might alter the course f disease are not possible due to the small size To that end we propose utilizing our state of the art gene editing platform to develop swine with a specific mutation P L corresponding to the human P L mutation of the MYO B gene present in Navajo MVID patients We hypothesize that introducing a Proline P to Leucine L mutation in pigs at a site analogous to the human P L allele can induce MVID in piglets Execution of the hypothesis can be accomplished with the following specific aim develop and evaluate the MYO B P L mutant pigs as models of human MVID In addition to state of the art gene editing platform with expertise of Drs Melkamu Veterinary Physiology and Carlson Animal biotechnology from Recombinetics we have engaged a world renown expert in MVID Dr James R Goldenring MD PhD a gastroenterologist and a Professor of Experimental Surgery from Vanderbilt University School of Medicine A reliable large animal model of MVID will have tremendous impact on industry and academic research to develop and test new drugs and novel therapeutic approaches to treat this awful disease PUBLIC HEALTH RELEVANCE This SBIR aims to develop a swine model of microvillus inclusion disease MVID the most severe cause of Congenital Diarrheal Diseases in neonates We use gene editing to mimic the most common and severe allele corresponding to the human P L mutation of the MYO B gene present in Navajo MVID patients There is still no cure for MVID besides parenteral nutrition and bowel transplants without which all patientsandapos progress into severe dehydration and death We propose that this unique large animal model will mimic the human condition and accelerate translation of novel therapies into the clinic