A Large Animal Model of SMA

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DESCRIPTION (provided by applicant): The purpose of these studies is to develop a pig animal model of Spinal Muscular Atrophy (SMA) whereby the development and testing of therapeutics can be efficiently accomplished. SMA, the most common inherited motor neuron disease, occurs in ~1:8,000 live births and has a carrier frequency of ~1:40; however, no cure exists. Currently there are ongoing efforts to develop SMA therapeutics using the available mouse models; however, these mouse models have limitations when considering therapeutic applications. The rapid and progressive postnatal phenotype makes it difficult to evaluate compounds and antisense oligonucleotides (ASOs) and to deliver and achieve expression of virally delivered therapeutics before the phenotype is too severe to change course. These difficulties are routinely discussed within the field, and as a result efforts have been made to develop alternative animal models. In addition, the biological differences between mouse and human make translational approaches difficult and sometimes impossible. It is anticipated that since the pig has many biological and physiological similarities to the developing human that a pig SMA model will more closely mimic the human condition. The availability of a large animal model for the development and validation of therapeutics would be of real significance for SMA and other neurodegenerative diseases. A number of translational programs are accelerating in SMA research, including small molecules, gene therapy and ASOs. Small molecules have a relatively well-defined pathway for FDA approval; however, it is likely that novel biologics such as gene therapy, antisense RNAs and cellular therapies will be greatly enhanced once blood-brain barrier permeability, dosing, delivery, distribution, sustainability and the immune response can be examined in a larger-animal model of disease such as an SMA pig. With no large SMA model available, SMA investigators have been turning to wildtype monkeys and pigs to analyze delivery and distribution without the ability to demonstrate efficacy. And while wildtype large animals can be used for distribution studies, the cellular and tissue differences between SMA and wildtype individuals could significantly impact these outcome measures. The development of a pig SMA model would allow researchers the ability to perform efficacy and delivery-related studies in a single large model and efficiently traverse from bench to bedside. PUBLIC HEALTH RELEVANCE: SMA (Spinal Muscular Atrophy) is the most common inherited motor neuron disease and occurs in ~1:8,000 live births and has a carrier frequency of ~1:40; however, no cure exists. This proposal is aimed at developing a large animal model of SMA in order to better develop and understand the effectiveness of drug, stem-cell and gene therapies. Pigs are well-suited animal models for a number of critical reasons including the similarity between human and pig development, metabolism and organ systems; therefore, the development of a pig SMA model would provide unique benefits for the SMA community as the field pushes toward a cure.