Novel Approaches for Correcting Respiratory Insufficiency in Pompe Disease

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DESCRIPTION (provided by applicant): Dr. El Mallah is an Assistant Professor of Pediatrics, Pediatric Pulmonary Division, University of Florida, with 75% of time devoted to research, 25% to clinical. During the proposed award, her career development and learning objectives are to 1) acquire core knowledge in respiratory neurobiology and molecular therapy, 2) gain further expertise in research methodology, techniques, and scientific writing, and 3) develop academic leadership skills. Dr. El Mallah's long-term career goal is to become a successful independent pediatric pulmonary clinician scientist with an emphasis on translational research. As a result of her research she has published her findings, presented them at national meetings and has received several awards and grants, including the Parker B. Francis fellowship award. ENVIRONMENT: Drs. Fuller and Byrne are exceptional mentors, with a track record of successful mentees. Dr. Fuller is a leader in respiratory neurobiology, while Dr. Byrne is a national gene therapy expert. They both have extensive NIH funding, very active and productive laboratories, and will provide the resources to assist the candidate in her research project. The University of Florida (UF) Pediatric Department offers a structured scholars program designed to enhance research and leadership skills, and to give structured feedback and evaluations. UF also offers an employee education program to support coursework for the candidate. RESEARCH: The research project in this proposal will build on the candidate's prior research on targeting respiratory dysfunction in Pompe disease. In addition, it will explore a novel therapeutic agent for stimulating respiratory drive in a Pompe (Gaa-/-) mouse model. Pompe disease is a fatal neuromuscular disorder resulting from mutations in the gene for acid alpha- glucosidase (GAA) - an enzyme necessary to degrade lysosomal glycogen. Infants with Pompe disease suffer with respiratory insufficiency often leading to mechanical ventilation. Breathing problems have originally been attributed to muscle pathology but our group has recently shown a central nervous system contribution. Unfortunately, the only FDA approved therapy for Pompe disease (enzyme replacement therapy) is suboptimal because it does not cross the blood brain barrier. Therefore, many patients on enzyme replacement therapy still require mechanical ventilation. We propose a series of pre-clinical studies that directly address the need for treatment of the CNS in Pompe disease. Specifically, we will evaluate the therapeutic efficacy of ampakines, compounds that enhance excitatory glutaminergic neural transmission in respiratory neurons. In addition, since ampakines do not directly address the underlying pathology, we will use gene delivery to correct the underlying gene defect. Alone, gene delivery does not transduce the entire motoneuron pool and appears to only partially correct neural dysfunction. Therefore we propose to study the impact of ampakines on respiratory function following AAV gene therapy in Pompe mice in order to optimize therapy for respiratory dysfunction. Overall, this project will test an important and novel hypothesis and will provide the candidate with training in new experimental techniques. The fundamental hypothesis driving this proposal is that ampakine therapy will potentiate respiratory motor output in Pompe disease, and the function of these drugs will be further enhanced after CNS GAA activity is increased via AAV-based gene therapy. This will be examined using two specific aims: Aim 1: To test the hypothesis that ampakine therapy will stimulate respiratory drive in a mouse model of Pompe disease. Aim 2: To test the hypothesis that the efficacy of ampakine therapy will be further enhanced after CNS GAA activity is increased via AAV-based gene therapy. PROJECT RELEVANCE: This work is innovative because the impact of these excitatory agents, ampakines on respiratory dysfunction has not been evaluated in the context of neuromuscular disorders. Moreover, the ampakine treatments, which definitively work via a neural mechanism, will serve to emphasize the neural contribution to respiratory dysfunction in Pompe mice, and the necessity to target the CNS in order to treat this fatal disease. In addition, since both ampakines and AAV-GAA have already undergone phase I and II clinical trials and are safe for human use, this work has the strong potential to quickly translate to human care and to impact the clinical treatment of Pompe disease.