Engineered Neuroprotective Stem-Cell Exosomes for In Utero Spina Bifida Therapy

用于子宫内脊柱裂治疗的工程神经保护干细胞外泌体

• 批准号: 10705047
• 负责人: Diana Lee Farmer
• 金额: $ 50.74万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705047
• 关键词: Achievement; Animal Model; Animals; Binding; Biocompatible Materials; Biomedical Engineering; Birth; Bladder Dysfunction; Bone Diseases; Bone Regeneration; Caring; Cell Communication; Cells; Chemical Injury; Child; Childhood; Clinical; Clinical Trials; Collagen; Defect; Deformity; Disease; Engineering; Environment; Exposure to; Fetal Development; Fetal Sheep; Fetal Tissues; Glycolic-Lactic Acid Polyester; Goals; Growth; Health Care Costs; Human; Hydrogels; Hydroxyapatites; Immobilization; In Vitro; Intestines; Kyphosis deformity of spine; Limb structure; Longevity; Mechanics; Meningomyelocele; Mesenchymal; Methods; Modeling; Molecular; Molecular Weight; Morbidity - disease rate; Motor; Muscle; Musculoskeletal; Neural Tube Closure; Neurodegenerative Disorders; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Outcome; Paralysed; Patients; Peptides; Physical therapy; Play; Preventive care; Quality of life; Recovery of Function; Regimen; Rodent; Role; Speed; Spinal Cord; Spinal Dysraphism; Spinal cord injury; Surface; System; Testing; Therapeutic; Therapeutic Uses; Transplantation; Trauma; United States; United States National Institutes of Health; Vertebral column; Walking; biodegradable polymer; bioscaffold; bone; bone scaffold; cognitive disability; density; design; dosage; embryo surgery; exosome; experimental study; extracellular vesicles; fetal; functional group; hindbrain; improved; in utero; in vivo; independent ambulation; mechanical properties; neuroprotection; novel; novel strategies; novel therapeutics; paracrine; postnatal; pre-clinical; prenatal therapy; prevent; regeneration function; regeneration potential; regenerative; regenerative therapy; repaired; scaffold; sheep model; spinal cord compression; standard of care; stem cell exosomes; stem cells

ABSTRACT Myelomeningocele (MMC) is the most severe form of spina bifida (SB) and the most common congenital cause of lifelong paralysis in the United States, where approximately four children are born daily with this devastating disease. MMC results from the incomplete closure of the neural tube and absent overlying spine leaving the spinal cord exposed to intrauterine mechanical and chemical trauma. This trauma results in lifelong paralysis, bowel and bladder dysfunction, musculoskeletal deformities, and cognitive disabilities due to hindbrain herniation. In utero surgical repair improves morbidity, but functional recovery is incomplete and the majority of children are still unable to walk independently. We developed a treatment for MMC that augments the standard of care, in utero MMC surgical repair, with placental mesenchymal stromal/stem cells (PMSCs). We found that treatment with PMSCs, during in utero repair, prevents hind limb paralysis in the well-established fetal ovine model of MMC, due to PMSC paracrine secretion of neuroprotective factors. However, we confirmed that PMSCs did not engraft long-term and treated lambs developed severe kyphosis causing spinal cord compression and tethering due to the lack of bone and adjacent paraspinal muscles, which is consistent with human MMC musculoskeletal deformities. To meet this need for a long-lasting therapy for MMC, we explored the use of bioengineered multifunctional combination scaffolds. Exosomes are extracellular vesicles that play significant roles in cell-to cell communication. We confirmed that exosomes secreted by PMSCs (PMSC-exosomes) exert significant neuroprotective functions, similar in magnitude to the live PMSCs from which they are derived. In this study, we propose to develop an engineered hydrogel system that will allow for both local and sustained release of PMSC-exosomes to the spinal cord, which in turn will provide sustained neuroprotection to treat MMC before birth. In addition, we aim to increase the longevity of the in utero treatment by covering the defect with a biomaterial-based bony scaffold to provide structural and functional support. We plan to optimize the neuroprotective and regenerative functions of the bioscaffold using our well-established fetal rodent and rabbit models of MMC. We will evaluate the final combination multifunctional bioscaffold product in our gold-standard fetal ovine model of MMC. This therapeutic will be cell-free, off-the-shelf, and easy-to-use. If successful, this novel approach will be used to treat MMC before birth, and due to its regenerative qualities, the treatment will improve the quality of life of these patients, as well as significantly lower the healthcare costs associated with the current treatment.

抽象的 脊髓脑膨出（MMC）是脊柱裂（SB）最严重的形式，也是最常见的先天性原因 在美国终身瘫痪，每天大约有四个孩子出生于这个毁灭性的 疾病。 MMC是由于神经管的不完全闭合而导致的 脊髓暴露于宫内机械和化学创伤。这种创伤导致终身瘫痪， 肠和膀胱功能障碍，肌肉骨骼畸形和因后脑引起的认知障碍 疝气。在子宫内手术维修中，可提高发病率，但功能恢复不完整，大多数 孩子们仍然无法独立行走。我们为MMC开发了一种增强标准的治疗方法 在子宫MMC手术修复中，带有胎盘间充质基质/干细胞（PMSC）。我们发现 在子宫修复期间，用PMSC治疗可防止后肢瘫痪在良好的胎儿卵中 MMC的模型，由于PMSC旁分泌神经保护因子的分泌。但是，我们确认PMSCS 没有长期植入和治疗的羔羊出现严重的脑脚，导致脊髓压缩和 由于缺乏骨骼和邻近的椎旁肌肉而束缚，这与人类MMC一致 肌肉骨骼畸形。为了满足对MMC长期疗法的需求，我们探索了 生物工程多功能组合脚手架。外泌体是细胞外囊泡 在细胞到细胞通信中的作用。我们确认由PMSC（PMSC-exosomes）分泌的外泌体施加 显着的神经保护功能，大小与它们得出的活性PMSC相似。在这个 研究，我们建议开发一种工程的水凝胶系统，该系统将允许局部和持续释放 脊髓的PMSC-诊断症，这反过来将提供持续的神经保护以治疗MMC 出生。此外，我们旨在通过用A覆盖缺陷来增加子宫内治疗的寿命 基于生物材料的骨支架，提供结构和功能支持。我们计划优化 使用我们建立良好的胎儿啮齿动物和兔子的生物遵循的神经保护性和再生功能 MMC的模型。我们将评估黄金标准的最终组合多功能生物效应产品 MMC的胎儿烤箱模型。这种治疗性将无细胞，现成且易于使用。如果成功，这 新颖的方法将在出生前用于治疗MMC，并且由于其再生品质，治疗将会 提高这些患者的生活质量，并大大降低与 当前的治疗。