Developing second generation SCID pig models: filling the gaps to improve translation of therapeutics in regenerative medicine

项目总结/摘要 大型动物模型是开发再生医学疗法和最大限度地安全转化的关键 临床，因为FDA建议提供小型和大型动物模型的数据，以批准此类 治疗使用R24资金（OD 019813），我们开发了生物防护设施和协议，以提高Artemis 在一个实施方案中，本发明提供了一种具有DCLRE 1C突变的SCID猪模型（ART）以及也具有IL 2 RG突变的改进的模型（ART-IL 2 RG）。使用SCID 临床前研究中的猪模型需要能够安全地将健康的SCID猪运送到美国各地， 有兴趣的科学家谁没有能力提高这样的猪自己。以下两个目标解决了这一问题 SCID猪研究领域存在的不足： 目标1。创建在HEPA过滤隔离器内安全运输SCID猪的方法， 美国和加拿大研究人员的预告片 目标2.通过建立一个临时设施和购买专门的设备，改善SCID猪的生物安全性和健康状况。 消毒设备 由于没有既定的方法在运输SCID猪的同时保持生物封闭，目标1的工作将集中在 一个由定制拖车和内部隔离器组成的运输系统的开发将使这一点变得至关重要 下一步可能。需要可移动的内部隔离器来安全地安置SCID猪，以及缩短- 从设施生物防护气泡到无菌拖车的长途运输。 此外，该修订计划扩大了可以使用SCID猪的客户类型，因为隔离器包含SCID猪 可在外部站点维护，用于短期研究。在目标2中，我们继续开发有效的 方案的SCID猪饲养，并已确定，隔离器是一个有用的辅助原来提出的， 确认气泡程序。通过添加一种添加剂，SCID猪的生物安全性将得到显著改善 设施和购买专用的过氧化氢蒸发器，其尺寸足以对这些新空间进行灭菌， 设备.我们建议使用A&R资金来翻新现有生物防护泡沫附近的未使用空间， 提供这一设施，并将SCID猪舍的生物安全水平提高到行业标准。的 灭菌设备，包括能够处理现有气泡的专用过氧化氢蒸发器 以及目标1中建议的新运输方法，由于现有设备不足，因此迫切需要。的 拟议的补充目标并没有扩大现有母公司补助金的范围，而是直接回应了这一呼吁 A&R补充剂。

Project Summary/Abstract Large animal models are critically needed to develop regenerative medicine therapeutics and maximize safe translation to the clinic, as the FDA recommends data be provided on both small and large animal models for approval of such therapies. Using R24 funding (OD019813), we developed biocontainment facilities and protocols to raise an Artemis (DCLRE1C) mutant SCID pig model (ART) as well as an improved model also mutant in IL2RG (ART-IL2RG). The use of SCID pig models in preclinical research necessitates the ability to safely ship healthy SCID pigs across the United States to interested scientists who do not have the ability to raise such pigs themselves. The following two Aims address this existing deficit in the SCID pig research field: Aim 1. Create methods to safely transport SCID pigs within a HEPA filtered isolator transported in a HEPA filtered trailer to researchers in the US and Canada Aim 2. Improve the biosecurity and health of SCID pigs by creating a shower-in facility and purchase dedicated sterilization equipment. As there is no established method to ship SCID pigs while maintaining biocontainment, work in Aim 1 will focus on development of a transportation system consisting of a customized trailer and internal isolators will make this critical next step possible. The transportable internal isolators are needed both to safely house the SCID pigs as well as short- distance transportation from facility biocontainment bubbles to the sterilized trailer for long-distance transport. Further, this revised plan expands the type of clientele who can use the SCID pig, as the isolators containing the SCID pig can be maintained at an external site for short-term research studies. In Aim 2, we continue to develop effective protocols for SCID pig rearing and have identified that isolators are a useful adjunct to the originally proposed and validated bubble procedures. Biosecurity of the SCID pigs will be dramatically improved by the addition of a shower-in facility and purchase of dedicated hydrogen peroxide vaporizer adequately sized for sterilizing these new spaces and equipment. We propose to use A&R funds to renovate unused space adjacent to the existing biocontainment bubbles to provide this shower-in facility and raise the level of biosecurity for SCID pig housing to the industry standard. The sterilization equipment, consisting of a dedicated hydrogen peroxide vaporizer capable of handling the existing bubbles and the proposed new transportation approach in Aim 1, is critically needed as existing equipment is inadequate. The proposed Supplemental Aims do not expand the scope of the existing parent grant and are directly responsive to the call for A&R supplements.