Translating CNS therapies for the NCLs from rodent models to humans

University Of Iowa, Iowa City IA

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Abstract

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): 15-NS-103, 'Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease.'Children with inherited lysosomal storage disorders (LSDs) affecting the central nervous system (CNS) succumb to disease because of lack of therapeutic options. Although these diseases result from deficiency of soluble lysosomal enzymes, and systemic administration is effective for correction of peripheral organs, methods for treating the brain are few. Presently, repetitive direct introduction of recombinant enzyme, introduction of stem cells, or multiple injections of recombinant viruses are being investigated as therapies. We have recently developed two complimentary approaches to achieve enzyme correction in brain, and shown efficacy in mouse models of LSD. In one method, we demonstrated that a single injection of adeno-associated virus (AAV) vector with tropism to the ventricular lining ependymal cells corrected the storage disease and reversed established behavioral deficits throughout the CNS. In a second series of the studies, we identified peptide epitopes that homed to the brain, and cloned these epitopes into the AAV capsid. When injected into the peripheral vasculature, the resultant peptide-modified AAVs were redirected from principally targeting hepatocytes, to target also the cerebrum, cerebellum, brain stem and spinal cord. As a result, established neuropathological and behavioral deficits were corrected. Both of these novel approaches show remarkable promise and their development into translational programs would benefit greatly from testing in large animal models. Thus, this proposal will combine the Davidson's laboratory expertise in vector development and delivery with the Katz and Coates laboratories expertise in canine models of human disease. In recent work Katz and Coates have characterized a canine model of late infantile ceroid lipofuscinosis (LINCL), resulting from mutations in the gene encoding tripeptidyl peptidase I (TPP1). This model shows progressive neurological disease and pathological hallmarks that closely mirror LINCL. As stated in the RFA, the challenge is to enter into the NINDS translational research program. Our published data, and evidence presented here demonstrating efficacy of the approaches in the LINCL mouse model supports the proposed research to establish proof-of-concept in the canine model of LINCL. In this work we will test the safety and efficacy of gene therapies designed to correct central nervous system manifestations in a dog model of childhood-onset neurological diseases. These studies are an important step in a translational research program encompassing established investigators and new trainees at the University of Iowa and the University of Missouri, which builds upon preliminary work in rodent models showing robust improvements in behavioral manifestations and neuropathology shortly introduction of therapeutic vectors.