OPTIMIZATION AND ASSESSMENT OF A BIOLOGIC TO IMPROVE FUNCTIONAL RECOVERY AFTER PERIPHERAL NERVE INJURY

优化和评估生物制剂以改善周围神经损伤后的功能恢复

• 批准号: 10011899
• 负责人: Edmund Nesti
• 金额: $ 38.94万
• 依托单位: ALCAMENA STEM CELL THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011899
• 关键词: Address; Affect; Afferent Neurons; Affinity; Allografting; Axon; Binding; Biological; Biological Assay; C-terminal; Cell Culture Techniques; Cells; Clinical; Defect; Dose; Elements; Ensure; Gene Expression; Gene Silencing; Genes; Goals; Health Sciences; Human; In Vitro; Individual; Injury; Kinetics; Left; Libraries; Mediating; Membrane Potentials; Mesenchymal Stem Cells; Methods; Microscopy; Modeling; Motor; Motor Neurons; Muscle; Natural regeneration; Nerve; Nerve Regeneration; Neurons; Nuclear; Operative Surgical Procedures; Patients; Peptide aptamers; Peptides; Peripheral nerve injury; Permeability; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Preparation; Process; Proteins; Quantitative Reverse Transcriptase PCR; Randomized; Rattus; Recovery; Recovery of Function; Resources; Ribosomes; Rodent Model; Running; Scientist; Sensory; Signal Transduction; Site; Slice; Solubility; Specificity; Spinal Cord; Spinal Ganglia; Structure; Testing; Therapeutic; Time; Tissues; Toxicokinetics; Toxicology; Transcription Repressor; Trauma; Trauma patient; Tube; Universities; University Health Services; Western Blotting; aptamer; axon growth; axon guidance; base; combat; drug candidate; experience; experimental study; functional disability; improved; in vivo; injured; mutant; nerve autograft; nerve injury; nerve supply; neurotrophic factor; overexpression; peptidomimetics; prevent; protein aminoacid sequence; protein expression; protein phosphatase inhibitor-1; protein purification; regenerative; relating to nervous system; release factor; repaired; scaffold; sciatic nerve; stem cell therapy; transcription factor

ABSTRACT. Peripheral nerve injury (PNI) is a common and challenging clinical problem affecting over 3% of U.S. trauma patients. Among combat trauma, the rate of PNI increases to 22%. These patients require extensive resources for initial treatment and therapy, yet they are still left with functional disability. Current treatments for motor, sensory, and mixed PNI include nerve autografts and axonal guidance tubes. However, these methods do not restore complete function in injured patients. Full recovery requires re-innervation of muscle tissue after injury. A major impediment to regeneration is the lack of neurotrophic factor (NTF) release in the injured nerves. The reduction of NTF genes is due to injury-induced overexpression of the Repressor Element-1 Silencing Transcription (REST) factor. In addition, REST represses the expression of a host of neural specific genes required for proper function. To address this challenge, we developed the REST peptidomimetic peptide (RPP), which silences REST activity by inhibiting the specific phosphatase required to maintain its stability, the C- terminal domain small phosphatase 1 (CTDSP1). We demonstrate that RPP increases NTF expression in trauma-induced mesenchymal progenitor cells (TI-MPCs) and that it has great potential to stimulate nerve regeneration in PNI. In this proposal we will optimize the RPP and conduct a comprehensive nonclinical assessment in the following AIMS: AIM 1: OPTIMIZATION OF OUR HIGH AFFINITY CTDSP1 INHIBITOR. AIM 2: ASSESSING THE REGENERATIVE POTENTIAL OF DRUG CANDIDATES. To accomplish these objectives, Alcamena Stem Cell Therapeutics, LLC is collaborating with field leading academic scientists at Johns Hopkins University (JHU), and the Uniformed Services University of the Health Sciences (USHS/DoD). Cumulatively, these studies will inform us on the degree to which our drug candidate improves neuron regeneration, survival and function. Additionally, the use of both human injury induced mesenchymal stem cells and an in vivo rodent model of PNI ensure that our results are translatable towards our long-term goal of addressing the unmet therapeutic needs of PNI patients.

摘要。周围神经损伤（PNI）是一种常见的和具有挑战性的临床问题，影响超过3%的 美国创伤病人在战斗创伤中，PNI的比例增加到22%。这些患者需要大量的 他们没有足够的资源进行初步治疗和治疗，但仍然有功能残疾。的当前治疗 运动、感觉和混合PNI包括神经自体移植物和轴突引导管。但这些方法 不能完全恢复受伤患者的功能。完全恢复需要肌肉组织的神经支配， 损伤再生的一个主要障碍是受伤神经中缺乏神经营养因子（NTF）释放。 NTF基因的减少是由于损伤诱导的阻遏元件-1沉默的过度表达 转录（REST）因子。此外，REST抑制了许多神经特异性基因的表达， 需要适当的功能。为了应对这一挑战，我们开发了REST肽模拟肽（RPP）， 其通过抑制维持其稳定性所需的特异性磷酸酶来沉默REST活性， 末端结构域小磷酸酶1（CTDSP 1）。我们证明，RPP增加NTF的表达， 创伤诱导的间充质祖细胞（TI-MPCs），它具有刺激神经的巨大潜力， PNI的再生。在本提案中，我们将优化RPP，并进行全面的非临床 在以下AIMS中进行评估： 目的1：优化我们的高亲和力CTDSP 1抑制剂。 目的2：评估候选药物的再生潜力。 为了实现这些目标，Alcamena Stem Cell Therapeutics，LLC正在与该领域的领先企业合作， 约翰霍普金斯大学（JHU）和美国卫生部统一服务大学的学术科学家 科学（USHS/DoD）。累积起来，这些研究将告诉我们我们的候选药物 改善神经元再生、存活和功能。此外，使用这两种人体损伤诱导 间充质干细胞和PNI的体内啮齿动物模型确保了我们的结果可以转化为我们的研究结果。 解决PNI患者未满足的治疗需求的长期目标。