Generation of Tissue Engineered Nerve Grafts from GalSafe Porcine Neurons

利用 GalSafe 猪神经元生成组织工程神经移植物

基本信息

批准号：
10268167
负责人：
Kritika Katiyar
金额：
$ 93.41万
依托单位：
AXONOVA MEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10268167
关键词：
3-Dimensional Address Animal Model Antigens Autologous Transplantation Axon Benchmarking Biological Biological Products Biomanufacturing Biomass Brachial plexus structure Caring Cells Clinical Clinical Trials Cryopreservation Cyclic GMP Data Defect Distal Distant Ensure Face Family suidae Galactose Generations Genetic Engineering Gold Graft Survival Growth Hand Harvest Health Human Image Immune response Implant In Vitro Injury Lactate Dehydrogenase Lead Length Lesion Licensing Life Measures Medical Metabolic Methods Modeling Motor Nerve Nerve Regeneration Nervous System Trauma Neurodegenerative Disorders Neurons Operative Surgical Procedures Outcome Patients Peripheral nerve injury Phase Population Probability Process Protocols documentation Quality of life Recovery Recovery of Function Rodent Rodent Model Small Business Innovation Research Grant Source Stains Sterility Stretching Target Populations Techniques Testing Tissue Engineering Translations Transplantation Transportation Trauma Upper arm Validation afferent nerve axon regeneration base biofabrication clinical practice clinical translation complement system cost density efficacy study efficacy testing functional restoration immunocytochemistry improved in vivo injury and repair meetings nerve autograft next generation porcine model pre-clinical preservation product development programs quality assurance reconstruction regenerative reinnervation repaired research clinical testing safety study scaffold success

项目摘要

PROJECT SUMMARY Tissue engineered medical products have tremendous promise to address the currently irreparable effects of neurotrauma and/or neurodegenerative diseases. Axonova Medical’s lead product, the tissue engineered nerve graft (TENG), is a bioactive “living scaffold” proven to promote rapid nerve regeneration and functional restoration when implanted to repair major peripheral nerve injury (PNI). Implementing living neuronal cells as the starting biomass, Axonova routinely biomanufactures TENGs comprised of living, long, aligned axon tracts through the proprietary process of axon “stretch-growth”. To date, TENGs have been shown to consistently promote host axon regeneration and improve functional recovery compared to current clinical practices in both small and large animal models of PNI, including the repair of 5 cm segmental defects. In order to move to a manufacturing- compliant biomass, Axonova has partnered with Revivicor to generate GalSafe® TENGs using their genetically engineered porcine neurons to mitigate a host immune response upon eventual transplantation in humans. Through the Phase I efforts, GalSafe® TENGs were successfully stretch-grown to create products at lengths of 1 cm, 3 cm, and 5 cm with a health and axon density that met or exceeded established quality benchmarks. Moreover, 1 cm TENGs were transplanted into a rodent PNI model to demonstrate regenerative efficacy, revealing that GalSafe® TENGs survived as well as actively drove host axonal regeneration via the proprietary mechanism-of-action of TENGs, referred to as axon facilitated axon regeneration (AFAR). Along with choosing a safe and readily available starting biomass, other product development challenges include biopreservation and quality assurance criteria to allow increased shelf life, transportation, and maintained efficacy of the product. Accordingly, the current Phase II SBIR program addresses a key facet of clinical grade biomanufacturing, specifically the validation of an effective storage protocol and release criteria ensuring product health, sterility, and potency. TENGs will be biofabricated from a cGMP-compliant cell source (GalSafe® porcine neurons), cold- stored using a cGMP-compliant preservation protocol, and then tested in small and large animal models of PNI to demonstrate regenerative efficacy. Specifically, Axonova will systematically complete the objectives of this program across 3 Specific Aims: (1) determine the efficacy of fresh GalSafe® TENGs in an established porcine PNI model; (2) effectively biopreserve GalSafe® TENGs to increase shelf-life and validate non-invasive release criteria; and (3) determine the potency and efficacy of biopreserved GalSafe® TENGs in vivo in rodent and porcine PNI models. This program addresses a major challenge in the translation of next-generation tissue engineered medical products by validating manufacturing, storage and release criteria for a living biological product to enable eventual testing in humans. The ability to store and distribute GalSafe® TENGs as an “off-the- shelf” product will vastly increase commercial potential by reducing costs and expanding patient access, thereby improving recovery and quality of life for patients suffering from the debilitating effects of major PNI.

项目概要组织工程医疗产品对于解决目前不可挽回的影响有着巨大的前景 Axonova Medical 的主导产品——组织工程神经。移植物（TENG）是一种生物活性“活支架”，被证明可以促进神经快速再生和功能恢复当植入以修复主要周围神经损伤（PNI）时，以活神经元细胞作为起始。生物质，Axonova 常规生物制造 TENG 由活的、长的、对齐的轴突束组成，通过迄今为止，TENG 已被证明能够持续促进宿主的生长。与目前小型和大型临床实践相比，轴突再生并改善功能恢复 PNI 动物模型，包括修复 5 厘米节段性缺陷，以便进入制造阶段。合规生物质，Axonova 与 Revivicor 合作，利用其基因生成 GalSafe® TENG 改造猪神经元以减轻最终移植到人体后的宿主免疫反应。通过第一阶段的努力，GalSafe® TENG 已成功拉伸生长，以制造出长度为 1 厘米、3 厘米和 5 厘米，其健康状况和轴突密度达到或超过既定的质量基准。此外，将1厘米的TENGs移植到啮齿动物PNI模型中以证明再生功效，揭示 GalSafe® TENG 存活下来并通过专有技术积极驱动宿主轴突再生 TENG 的作用机制，称为轴突促进轴突再生 (AFAR)。安全且易于获得的起始生物质，其他产品开发挑战包括生物保存和质量保证标准，以提高产品的保质期、运输和维护效率。因此，当前的 II 期 SBIR 计划解决了临床级生物制造的一个关键方面，特别是有效的储存协议和放行标准的验证，确保产品健康、无菌、 TENG 将由符合 cGMP 的细胞来源（GalSafe® 猪神经元）、冷-生物制造。使用符合 cGMP 的保存方案进行保存，然后在小型和大型 PNI 动物模型中进行测试具体来说，Axonova 将系统地完成这一目标。该计划涵盖 3 个具体目标：(1) 确定新鲜 GalSafe® TENG 在已建立的猪体内的功效 PNI 模型；(2) 有效地生物保存 GalSafe® TENG，以延长保质期并验证非侵入性释放标准；(3) 确定生物保存的 GalSafe® TENG 在啮齿动物体内的效力和功效该计划解决了下一代组织转化的主要挑战。通过验证活生物体的制造、储存和释放标准来设计医疗产品能够在人体中进行最终测试能够将 GalSafe® TENG 作为“现成的”进行存储和分发。 “货架”产品将通过降低成本和扩大患者使用范围来极大地增加商业潜力，从而改善遭受主要 PNI 衰弱影响的患者的康复和生活质量。