A Large Animal Model of SMA

描述（由申请人提供）：这些研究的目的是建立脊髓性肌萎缩症（SMA）的猪动物模型，从而有效地完成治疗方法的开发和测试。SMA是最常见的遗传性运动神经元疾病，发生在约1:8 000活产婴儿中，携带者频率约为1:40；然而，目前还没有治愈方法。目前，正在努力利用现有的小鼠模型开发SMA治疗方法；然而，这些小鼠模型在考虑治疗应用时存在局限性。快速和进行性的出生后表型使得很难评估化合物和反义寡核苷酸（ASOs），以及在表型过于严重而无法改变过程之前递送和实现病毒递送治疗的表达。这些困难在该领域经常被讨论，因此已经努力开发替代的动物模型。此外，小鼠和人类之间的生物学差异使得翻译方法变得困难，有时甚至不可能。由于猪与发育中的人类有许多生物和生理上的相似之处，因此猪SMA模型将更接近于模拟人类的状况。大型动物模型的可用性对SMA和其他神经退行性疾病的治疗方法的开发和验证具有真正的意义。一些转化项目正在加速SMA的研究，包括小分子、基因治疗和aso。小分子有一个相对明确的途径获得FDA的批准；然而，一旦能够在更大的动物疾病模型（如SMA猪）中检查血脑屏障的渗透性、剂量、递送、分布、可持续性和免疫反应，基因疗法、反义rna和细胞疗法等新型生物制剂可能会得到极大的增强。由于没有可用的大型SMA模型，SMA研究人员已经转向野生型猴子和猪来分析没有能力证明有效性的输送和分布。虽然野生型大型动物可以用于分布研究，但SMA和野生型个体之间的细胞和组织差异可能会显著影响这些结果测量。猪SMA模型的开发将使研究人员能够在单个大型模型中进行疗效和输送相关的研究，并有效地从实验室到床边。

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.