Stem cell-loaded microgels to treat discogenic low back pain

装载干细胞的微凝胶可治疗椎间盘源性腰痛

• 批准号: 10398627
• 负责人: Dmitriy Sheyn
• 金额: $ 165.57万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-27 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398627
• 关键词: Adult; Affect; Aftercare; Animal Model; Attenuated; Autopsy; Biocompatible Materials; Biological Assay; Biomanufacturing; Cell Differentiation process; Cell Survival; Cells; Chronic low back pain; Clinic; Complete Blood Count; Cyclic GMP; Data; Deposition; Development; Disease; Encapsulated; Ensure; Ethnic Origin; Evaluation; Fibrinogen; Gender; Goals; Health; Healthcare Systems; Helping to End Addiction Long-term; Hour; Human; Hydrogels; Hypersensitivity skin testing; Immunocompromised Host; In Vitro; Inflammation; Injectable; Injections; Injury; Intervertebral disc structure; Letters; Low Back Pain; Magnetic Resonance Imaging; Mechanics; Methods; Microencapsulations; Microfluidics; Minnesota; Modeling; Molds; Monitor; Morbidity - disease rate; Motor; Natural regeneration; Needles; Operating Rooms; Operative Surgical Procedures; Outcome; Outcome Measure; Outcome Study; Pain; Pain management; Patients; Phenotype; Population; Preparation; Procedures; Property; Protocols documentation; Puncture procedure; Race; Rattus; Readiness; Reproducibility; Reproducibility of Results; Research; Safety; Saline; Ships; Specialist; Spinal; Spinal Puncture; Sprague-Dawley Rats; Sterility; Stimulus; Surgeon; Symptoms; System; Technical Expertise; Techniques; Temperature; Testing; Time; Treatment Efficacy; Underserved Population; United States National Institutes of Health; Universities; Validation; Vertebral column; Videoconferencing; Xenograft procedure; biobehavior; cell bank; chronic back pain; conditioned place preference; cost; disability; discogenic pain; immunoreaction; in vivo; induced pluripotent stem cell; innovation; intervertebral disk degeneration; meetings; member; multidisciplinary; novel therapeutics; nucleus pulposus; preconditioning; prescription opioid; progenitor; reduce symptoms; regeneration potential; single-cell RNA sequencing; stability testing; stem cell therapy; stem cells; sterility testing; targeted treatment; therapeutic candidate; underserved community

PROJECT SUMMARY Low back pain (LBP) is a leading cause of disability and morbidity in the adult population, affecting approximately 80% of adults within their lifetime. Up to 40% of all low back pain is attributed to discogenic pain from IVD degeneration. While people of different races, ethnicity and gender suffer from chronic back pain, this disease has been shown to affect often people from underserved communities. IVD degeneration is known to affect the NP, the central part of the IVD. Despite decades of research, robust therapies targeting underlying causes rather than symptoms of IVD degeneration are still in the earliest stages of development. Conservative treatments alleviate symptoms rather than targeting the underlying disease. Stem cell therapy has been shown a great promise to regenerate IVD in animal models. Specifically, we have shown that induced pluripotent stem cells can be differentiated to notochordal cells (iNC), the original progenitors of NP cells. Different cell delivery and microencapsulation techniques will be explored to generate, iNC-microgel, preconditioned iNC-microgels and iNCs in bulk hydrogel. Cell purity, identity, viability and sterility data will be obtained. Furthermore, the material composition and properties will be investigated, and the stability of microencapsulated iNCs after preparation evaluated. Safety and efficacy of the therapeutic candidates will be evaluated in a rat model of IVD degeneration and discogenic low back pain, induced by disc puncture of the lumbar spine. After confirming successful induction of IVD degeneration, different therapeutic candidates and controls will be injected. The candidate’s regenerative potential and reproducibility of results will be evaluated by biobehavioral testing, MRI and immunohistochemical analyses. For mechanism of action studies, single cell RNA sequencing of the treated IVDs will be employed. The outcome of the study will be defined therapeutic candidate for low back pain stem cell therapy and multidisciplinary team including biologist, clinicians, translational experts and statisticians that will be set up for biomanufacturing and IND- enabling studies via U19 mechanism of the NIH HEAL initiative.

项目概要 腰痛 (LBP) 是导致成年人残疾和发病的主要原因，影响约 80% 的成年人 成年人一生中高达 40% 的腰痛是由 IVD 退化引起的。 不同种族、民族和性别的人都患有慢性背痛，这种疾病已被证明经常影响 尽管 IVD 退化会影响 NP，但 IVD 的核心部分。 经过数十年的研究，针对 IVD 退化原因而不是症状的强有力的治疗方法仍然处于研究阶段。 发展的早期阶段，保守治疗缓解症状，而不是针对潜在的疾病。 干细胞疗法在动物模型中显示出再生 IVD 的巨大前景。 诱导多能干细胞可以分化为脊索细胞（iNC），即NP细胞的原始祖细胞。 将探索细胞递送和微胶囊技术以生成 iNC-微凝胶、预处理的 iNC-微凝胶 此外，还将获得散装水凝胶中的细胞纯度、活力和无菌数据。 将研究其组成和性质，并在制备后评估微囊化 iNC 的稳定性。 候选治疗药物的安全性和有效性将在 IVD 变性和遗传低下的大鼠模型中进行评估 腰椎间盘穿刺引起的背痛在确认成功诱导 IVD 退变后， 将注射不同的治疗候选者和对照，候选者的再生潜力和再现性。 结果将通过生物行为测试、MRI 和免疫组织化学分析来评估作用机制。 研究中，将采用经过处理的 IVD 的单细胞 RNA 测序。 该研究的结果将确定腰痛干细胞疗法和多学科治疗的候选者 将为生物制造和 IND 组建的团队，包括生物学家、退伍军人、转化专家和统计学家 通过 NIH HEAL 计划的 U19 机制进行研究。