Brain-targeted delivery of therapeutic molecules by exosomes derived from engineered human iPS cells: a potential therapeutic approach for Huntington's disease

通过源自工程化人类 iPS 细胞的外泌体向大脑靶向递送治疗分子：亨廷顿病的潜在治疗方法

• 批准号: 10588392
• 负责人: Pan Li
• 金额: $ 26.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10588392
• 关键词: Affect; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Behavioral; Binding; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; CAG repeat; Cell secretion; Cells; Chemicals; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Corpus striatum structure; Cyclic GMP; Dedications; Development; Disease; Emotional; Encapsulated; Engineering; Foundations; Future; Genes; Glycoproteins; Human; Human Engineering; Huntington Disease; Huntington gene; Injections; Investigation; Knock-in Mouse; Length; Mesenchymal Stem Cells; Movement; Mus; Nerve Growth Factors; Neurodegenerative Disorders; Neurons; Pathway interactions; Patients; Penetration; Peptides; Procedures; Production; Property; Prosencephalon; Proteins; RNA; RNA Splicing; Rabies; Reporting; Small Interfering RNA; Solid; Source; Spinal Puncture; Surface; Testing; Therapeutic; Therapeutic Studies; Toxic effect; Translating; Translations; Treatment Efficacy; Viral; blood-brain barrier crossing; blood-brain barrier penetration; clinical application; clinical translation; delivery vehicle; disease phenotype; effective therapy; efficacy evaluation; efficacy study; exosome; extracellular; genome editing; homologous recombination; in vivo; individual patient; induced pluripotent stem cell; manufacture; mouse model; mutant; neurotoxic; neurotoxicity; neurotrophic factor; novel; novel therapeutic intervention; overexpression; phosphorodiamidate morpholino oligomer; polyglutamine; preclinical development; prevent; success; targeted delivery

PROJECT SUMMARY Huntington’s disease (HD) is a devastating neurodegenerative disease caused by a CAG repeat expansion in the gene huntingtin (HTT). The CAG repeat is translated into a polyglutamine (polyQ) tract in the mutant HTT protein that has neurotoxic properties. Current therapeutic efforts are focused at suppressing the expression of the mutant HTT protein or targeting downstream pathways of neurotoxicity. We and others have shown that CAG repeat-targeting phosphorodiamidate morpholino oligomers (PMOs) and neurotrophic protein BDNF have therapeutic benefits for HD. However, PMOs and BDNF do not usually cross the blood-brain barrier (BBB), hindering the translation of clinical application. Therefore, more efficient delivery vehicles capable of BBB penetration are critical for the development of effective therapies for HD and other neurodegenerative disorders in general. Exosomes (Exo) are cell-secreted extracellular vehicles with BBB penetration potential, capable of delivering exogeneous therapeutic molecules. iPSCs have been considered as one of the best sources for Exo manufacture, based on high Exo yield, availability of cGMP-compatible clinical-grade manufacture platform for iPSC production and Exo manufacture, and feasibility to perform genome editing to establish engineered iPSCs that produce modified Exo for more efficient brain targeting. We therefore propose to develop strategies to produce brain-targeting Exo from engineered iPSCs as delivery vehicles for PMOs as well as BDNF, and further rigorously study the therapeutic efficacy of the brain-targeting Exo loaded with PMOs and BDNF in a panel of HD neuron and mouse models. Success of this project will set the stage for future larger scale investigations aimed at using huma iPSC-derived Exo for targeted delivery of therapeutic molecules (such as PMOs, chemical compounds and neurotrophic factors) for various neurodegenerative disorders.

项目概要 亨廷顿病 (HD) 是一种毁灭性的神经退行性疾病，由 CAG 重复扩增引起 亨廷顿蛋白 (HTT) 基因在突变体 HTT 中被翻译成聚谷氨酰胺 (polyQ) 片段。 具有神经毒性的蛋白质目前的治疗努力集中在抑制的表达。 我们和其他人已经证明，CAG 突变的 HTT 蛋白或靶向神经毒性的下游途径。 重复靶向磷酸二酰胺吗啉寡聚物 (PMO) 和神经营养蛋白 BDNF 然而，PMO 和 BDNF 通常不会穿过血脑屏障 (BBB)， 阻碍了临床应用的转化，因此需要更高效的BBB运载工具。 渗透对于开发 HD 和其他神经退行性疾病的有效疗法至关重要 一般来说，外泌体 (Exo) 是细胞分泌的细胞外载体，具有 BBB 渗透潜力，能够 提供外源治疗分子的 iPSC 被认为是 Exo 的最佳来源之一。 制造，基于高 Exo 产量，cGMP 兼容的临床级制造平台的可用性 iPSC 生产和 Exo 制造，以及进行基因组编辑以建立工程化 iPSC 的可行性 因此，我们建议制定策略以实现更有效的大脑靶向。 利用工程 iPSC 生产脑靶向 Exo 作为 PMO 和 BDNF 的递送载体，并进一步 严格研究负载 PMO 和 BDNF 的脑靶向 Exo 在一组中的治疗效果 HD 神经元和小鼠模型的成功将为未来更大规模的研究奠定基础。 旨在利用人类 iPSC 衍生的 Exo 来靶向递送治疗分子（例如 PMO、化学物质） 化合物和神经营养因子）用于各种神经退行性疾病。