Cell specific delivery of novel therapies to enhance glomerular regeneration and repair

细胞特异性递送新疗法以增强肾小球再生和修复

• 批准号: 10675681
• 负责人: Stuart James Shankland
• 金额: $ 81.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675681
• 关键词: Affect; Age; Albuminuria; Animal Model; Cells; Cessation of life; Cicatrix; Clinical; Clinical Data; Clinical Trials; Deterioration; Disease; Epithelial Cells; Experimental Designs; Family; Focal and Segmental Glomerulosclerosis; Genes; Goals; Human; Innovative Therapy; Kidney; Kidney Diseases; Knowledge; Lead; Libraries; Methods; Molecular; Morphology; Mus; Natural regeneration; Organoids; Parietal; Patients; Peptides; Physiological; Process; Productivity; Proliferating; Recombinants; Renal function; Renal glomerular disease; Reporter; Research; Research Personnel; Safety; Technology; Testing; Therapeutic; Tissues; Transplantation; Urine; Work; blood filter; causal variant; cell injury; cell type; efficacy evaluation; epithelial stem cell; glomerular function; human data; in vivo; in vivo regeneration; injured; innovation; kidney biopsy; kidney cell; migration; nanobodies; novel; novel therapeutics; organoid transplantation; podocyte; preclinical development; prevent; progenitor; regeneration potential; repaired; self-renewal; small molecule; stem cells; stemness; targeted delivery; targeted treatment; therapeutic candidate; therapeutic development; tool

PROJECT SUMMARY/ABSTRACT The goal of this project is to change the treatment paradigm for proteinuric glomerular diseases by combining therapeutics development with cell-specific delivery to enhance podocyte repair and regeneration in vivo. Podocytes, highly specialized terminally differentiated epithelial cells, are injured in the majority of glomerular diseases. As podocytes cannot self-renew, podocyte loss leads to glomerular scarring. A subpopulation of parietal epithelial cells (PECs) can serve as podocyte stem cells (`PEC progenitors'), but their regenerative potential is insufficient to overcome disease-associated glomerular damage. Enhancing productive repair of podocytes thus requires a dual synchronized approach: (i) replacing lost podocytes to increase their number, and (ii) limiting/reversing damage to the remaining podocytes. However, major knowledge gaps prevent us from achieving these goals; these include our limited knowledge on the molecular factors stimulating PEC self-renewal and podocyte regeneration/repair, as well as options methods for delivering these factors to specific kidney cell types in vivo. Our team of four expert investigators will wield complementary tools to close these knowledge gaps and produce innovative therapies. Dr. Wessely will apply Design of Experiment (DoE) approaches to identify novel combinations of molecules that increase PEC progenitors and reduce podocyte loss; Dr. Roberts will conjugate these therapeutics to VHHs (nanobodies) for delivery to PEC progenitors and podocytes; Dr. Freedman will generate gene-edited human kidney organoids to validate effects of VHHs compared to clinical data from patients; Dr. Shankland will use lineage tracing animal models of podocyte depletion and human organoids transplanted into mouse kidneys for in vivo safety and efficacy analysis. This pipeline will ultimately test the hypothesis that targeted delivery of PEC- and podocyte-specific therapeutic cargos can enhance podocyte repair and regeneration in vivo, and restore glomerular function to below the clinical disease threshold. The work will be accomplished through two Specific Aims, each with unique Milestones. The first Aim is to increase glomerular regeneration in vivo by cell targeted delivery of novel combinations of peptides and small molecules to augment podocyte progenitors of parietal epithelial cell origin. The second Aim is to increase productive repair of damaged podocytes by cell-type specific delivery of newly identified therapies. For both aims, we will employ the above pipeline to discover candidate therapeutics by DoE and cross-referenced with glomerular disease signatures from human patients. These will be combined with cell type-specific VHHs from high diversity recombinant VHH libraries to selectively deliver them to human PECs (Aim 1), or podocytes (Aim 2). Enhanced regeneration in vivo will be demonstrated in animal models of FSGS and transplanted human organoids. This process will establish a new paradigm for the treatment of kidney disease, and produce lead therapeutic candidates for further pre-clinical development and ultimately human clinical trials.

项目概要/摘要 该项目的目标是通过结合以下方法来改变蛋白尿性肾小球疾病的治疗模式 通过细胞特异性递送来增强体内足细胞修复和再生的疗法开发。 足细胞是高度特化的终末分化上皮细胞，在大多数情况下都会受到损伤 肾小球疾病。由于足细胞不能自我更新，足细胞丢失会导致肾小球疤痕形成。一个 壁上皮细胞 (PEC) 亚群可以充当足细胞干细胞（“PEC 祖细胞”），但它们的 再生潜力不足以克服疾病相关的肾小球损伤。增强 因此，足细胞的有效修复需要双重同步方法：（i）替换丢失的足细胞以 增加它们的数量，以及（ii）限制/逆转对剩余足细胞的损害。然而，主要 知识差距阻碍我们实现这些目标；这些包括我们对分子的有限知识 刺激PEC自我更新和足细胞再生/修复的因素，以及选择方法 将这些因子传递到体内特定的肾细胞类型。 我们的四位专家调查员团队将利用补充工具来缩小这些知识差距，并 产生创新疗法。 Wessely 博士将应用实验设计 (DoE) 方法来识别新颖的 增加 PEC 祖细胞并减少足细胞损失的分子组合；罗伯茨博士将共轭 将这些疗法用于 VHH（纳米抗体），以递送至 PEC 祖细胞和足细胞；弗里德曼博士将 生成基因编辑的人类肾脏类器官，以与临床数据相比验证 VHH 的效果 患者; Shankland 博士将使用足细胞耗竭和人类类器官的谱系追踪动物模型 移植到小鼠肾脏中进行体内安全性和功效分析。该管道最终将测试 假设定向递送 PEC 和足细胞特异性治疗货物可以增强足细胞 体内修复和再生，并将肾小球功能恢复到临床疾病阈值以下。 这项工作将通过两个具体目标来完成，每个目标都有独特的里程碑。第一个目标是 通过细胞靶向递送肽和小分子的新型组合来增加体内肾小球再生 分子来增强壁上皮细胞起源的足细胞祖细胞。第二个目标是增加 通过新确定的疗法的细胞类型特异性递送对受损足细胞进行有效修复。对于两者 为了实现这一目标，我们将利用上述管道来发现能源部的候选疗法，并与 来自人类患者的肾小球疾病特征。这些将与来自细胞类型特异性的 VHH 相结合 高多样性重组 VHH 文库，选择性地将其递送至人类 PEC（目标 1）或足细胞（目标 2）。增强的体内再生能力将在 FSGS 动物模型和人体移植模型中得到证实 类器官。这一过程将为肾脏疾病的治疗建立新的范例，并产生铅 用于进一步临床前开发和最终人体临床试验的治疗候选药物。

项目成果

FSGS Recurrence Collaboration: Report of a Symposium.

FSGS 重复协作：研讨会报告。

• DOI: 10.1159/000535138
• 发表时间: 2024
• 期刊: Glomerular diseases
• 作者: Gipson,DebbieS;Wang,Chia-Shi;Salmon,Eloise;Gbadegesin,Rasheed;Naik,Abhijit;Sanna-Cherchi,Simone;Fornoni,Alessia;Kretzler,Matthias;Merscher,Sandra;Hoover,Paul;Kidwell,Kelley;Saleem,Moin;Riella,Leonardo;Holzman,Lawrence;Jackson,
• 通讯作者: Jackson,