Human Umbilical Cord as a Regenerative Meningeal Patch to Prevent Tethering and Improve Neurological Function Following In-Utero Spina Bifida Repair

人脐带作为再生脑膜贴片，可防止子宫内脊柱裂修复后束缚并改善神经功能

• 批准号: 10376879
• 负责人: Ramesha Papanna
• 金额: $ 65.19万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376879
• 关键词: 10 year old; Address; Affect; Age-Months; Allografting; Amniotic Fluid; Anatomy; Anterior Horn Cells; Anti-Inflammatory Agents; Arachnoid mater; Astrocytes; Axon; Biocompatible Materials; Biological; Biological Models; Birth; Blinded; Blood; Caregivers; Cattle; Cell Count; Cells; Cerebrospinal Fluid; Child; Cicatrix; Clinical; Clinical Trials; Clinical/Radiologic; Collagen; Cryopreservation; Data; Defect; Deterioration; Development; Diffusion Magnetic Resonance Imaging; Disease; Dura Mater; Economic Burden; Extravasation; FDA approved; Fostering; Foundations; Functional Magnetic Resonance Imaging; Goals; Growth; Health; Histologic; Human; Hyaluronic Acid; Incidence; Inflammation; Inflammatory Response; Label; Life; Live Birth; Magnetic Resonance Imaging; Maintenance; Measures; Meningeal; Meningomyelocele; Methodology; Methods; Mission; Morbidity - disease rate; Natural regeneration; Nerve; Nervous System Physiology; Neurologic; Neurological outcome; Operative Surgical Procedures; Ophthalmology; Outcome; Pain; Patients; Plant Roots; Pregnancy; Process; Property; Public Health; Publishing; Quality of life; Radiology Specialty; Reporting; Research; Research Personnel; School-Age Population; Site; Skin; Spinal Cord; Spinal Dysraphism; Spinal cord injury; Subarachnoid Space; Syringomyelia; Techniques; Testing; Texas; Therapeutic; Time; Tissues; Traction; Treatment Efficacy; Umbilical cord structure; United States; United States National Institutes of Health; Vertebral column; Walking; Work; astrogliosis; axon injury; base; comorbidity; contrast enhanced; cost; disability; fetal; functional outcomes; improved; improved outcome; in utero; indexing; innovation; insight; loss of function; mortality; novel; novel strategies; pre-clinical; preclinical study; pressure; prevent; protective effect; regenerative; regenerative repair; relating to nervous system; repaired; sheep model; skin patch; standard of care; success

SUMMARY Over half the children who underwent in-utero spina bifida repair are unable to walk, and over one-fourth of them require surgery for tethered spinal cord by school age. Methods to improve long-term spinal cord function and its co-morbidities for these patients, remains elusive. The long-term goal is to find in-utero spina bifida treatment approaches that address refinement of methodologies that will promote neurological and neurodevelopmental gains later in life, thereby functionally adjusting patients’ quality of life for the better. The objective of this proposal is to use a new approach to repair spina bifida in-utero in a sheep model system, which may render more beneficial outcomes for lambs over time than current methods of repair. A cryopreserved human umbilical cord (HUC), an allograft from a healthy term pregnancy following delivery, exerts anti- inflammatory and anti-scarring properties, synonymously crucial processes that directly impact whether spinal cord tethering will occur, and hence long-term outcomes. The HUC is currently FDA approved for ophthalmological diseases. In our preclinical studies, we have shown that use of the cryopreserved human umbilical cord as a meningeal patch helps regenerate the arachnoid layer, a key barrier to spinal cord infiltrating scar forming cells, ultimately reducing histological tethering and improving upon spinal cord function. Our central hypothesis is that the HUC, when used as a meningeal patch with two-layer closure during in-utero spina bifida repair, will improve long-term clinical outcomes compared to conventional repair or predicated biomaterials. This was formulated based on our preliminary data, representing a significant advancement in spina bifida treatment given clinical sequelae improvements, with the potential to vertically advance in-utero treatment. The rationale for this study is that there is an urgent critical need for an anti-scarring and regenerative matrix that can be placed as an intermediary layer between the spinal cord and skin layer to reduce tethering. The central hypothesis will be tested by pursuing three specific aims in a surgical spina bifida sheep model system with a myelotomy: 1) To compare long-term functional outcome differences between in-utero SB repair methodologies using a HUC vs. predicate (DurepairTM) biomaterial as a meningeal patch. 2) To quantify and compare long-term spatial and temporal changes of the spinal cord at defect repair sites for tethering, syringomyelia and inflammation using 3T MRI and diffusion tensor imaging. 3) To quantitatively compare the underlying mechanisms for long-term therapeutic efficacies of SB defect repair methodologies. We will pursue these aims using an innovative combination of surgical and biological manipulative techniques, since use of the cryopreserved human umbilical cord represents a new and substantive departure from the status quo by shifting focus to the anti-inflammatory, anti-scarring and regenerative repair of the meningeal coverings of spina bifida. The significance lies in the expected outcome from this work, that the human umbilical cord patch as a meningeal patch should be a viable longitudinal therapeutic option for spina bifida repair and support a human clinical trial.

概括 超过一半接受宫内脊柱裂修复术的儿童无法行走，超过四分之一的儿童无法行走。 他们需要在学龄前进行脊髓栓系手术，以改善长期脊髓功能。 以及这些患者的合并症仍然难以捉摸。长期目标是找到子宫内脊柱裂。 治疗方法旨在改进方法，以促进神经系统和 晚年神经发育的进步，功能上调整患者的生活质量，从而更好。 该提案的目标是使用一种新方法在绵羊模型系统中修复子宫内脊柱裂， 随着时间的推移，与目前的冷冻保存方法相比，可能会给羔羊带来更有益的结果。 人脐带（HUC）是来自健康足月妊娠分娩后的同种异体移植物，具有抗 炎症和抗疤痕特性，同义的关键过程，直接影响脊柱是否 脐带束缚将会发生，因此 HUC 目前已获得 FDA 批准。 在我们的临床前研究中，我们已经证明使用冷冻保存的人类。 脐带作为脑膜补片有助于蛛网膜层的再生，蛛网膜层是脊髓浸润的关键屏障 疤痕形成细胞，最终减少组织学束缚并改善我们的中枢功能。 假设 HUC 在子宫内脊柱裂期间用作具有两层闭合的脑膜补片 与传统修复或预测生物材料相比，修复将改善长期临床结果。 根据我们的初步数据制定，代表了脊柱裂治疗的重大进步 鉴于临床后遗症的改善，有可能垂直推进宫内治疗。 这项研究的重点是迫切需要一种可以放置的抗疤痕和再生基质 作为脊髓和皮肤层之间的中间层，以减少束缚。 通过在具有骨髓切开术的外科脊柱裂绵羊模型系统中追求三个特定目标来进行测试：1) 比较使用 HUC 与使用 HUC 的宫内 SB 修复方法之间的长期功能结果差异。 谓词 (DurepairTM) 生物材料作为脑膜斑块 2) 量化和比较长期空间和 使用 3T 进行脊髓栓系、脊髓空洞症和炎症缺陷修复部位的时间变化 MRI 和扩散张量成像 3) 定量比较长期的潜在机制。 我们将使用创新的方法来实现这些目标。 手术和生物操作技术的结合，因为使用了冷冻保存的人类脐带 脐带代表着对现状的新的实质性偏离，将重点转移到抗炎、 脊柱裂脑膜覆盖物的抗疤痕和再生修复的意义在于。 这项工作的预期结果是，人脐带补片作为脑膜补片应该是可行的 脊柱裂修复的纵向治疗选择并支持人体临床试验。