A Large Animal Model of SMA

描述（由申请方提供）：这些研究的目的是开发脊髓性肌萎缩症（SMA）的猪动物模型，从而可以有效地完成治疗药物的开发和测试。SMA是最常见的遗传性运动神经元疾病，发生率约为1：8，000活产婴儿，携带者频率约为1：40;然而，没有治愈方法。目前正在努力使用可用的小鼠模型开发SMA治疗剂;然而，这些小鼠模型在考虑治疗应用时具有局限性。快速和进行性的出生后表型使得难以评估化合物和反义寡核苷酸（ASO）以及在表型太严重而不能改变进程之前递送和实现病毒递送的治疗剂的表达。这些困难在本领域内进行了常规讨论，因此已经努力开发替代动物模型。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，有时甚至是不可能的。预期由于猪与发育中的人类具有许多生物学和生理学相似性，因此猪SMA模型将更接近地模拟人类状况。对于SMA和其他神经退行性疾病，开发和验证治疗方法的大型动物模型的可用性将具有真实的意义。SMA研究中的许多转化项目正在加速，包括小分子、基因治疗和ASO。小分子具有相对明确的FDA批准途径;然而，一旦可以在较大动物疾病模型（如SMA猪）中检查血脑屏障渗透性、给药、递送、分布、可持续性和免疫应答，新型生物制剂（如基因治疗、反义RNA和细胞治疗）可能会大大增强。由于没有大型SMA模型可用，SMA研究人员一直在转向野生型猴和猪来分析递送和分布，而无法证明疗效。虽然野生型大型动物可用于分布研究，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指标。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有效性和递送相关研究，并有效地从实验室到床边。 公共卫生相关性：SMA（脊髓性肌萎缩症）是最常见的遗传性运动神经元疾病，发生率约为1：8，000活产婴儿，携带者频率约为1：40;然而，目前尚无治愈方法。该提案旨在开发SMA的大型动物模型，以便更好地开发和了解药物，干细胞和基因疗法的有效性。由于许多关键原因，猪是非常适合的动物模型，包括人和猪发育、代谢和器官系统之间的相似性;因此，随着该领域向治愈方向发展，猪SMA模型的开发将为SMA群体提供独特的益处。

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.