A cross-species preclinical platform to enhance the translation of new medicines

加强新药转化的跨物种临床前平台

基本信息

批准号：
10699196
负责人：
Nicholas Andrew Geisse
金额：
$ 32.46万
依托单位：
CURI BIO INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10699196
关键词：
Address Adverse effects Affect Animal Model Animal Testing Animals Biological Biological Assay Biology CRISPR correction Calcium Cell Line Cells Cessation of life Clinic Clinical Clinical Trials Complex Data Dependovirus Development Disease Disease Progression Disease model Dose Duchenne muscular dystrophy Dystrophin Engineering Enzyme-Linked Immunosorbent Assay Ethical Issues Exhibits Failure Functional disorder Gene Expression Genes Genetic Medicine Heart failure Human Human Biology In Vitro Individual Life Link Marketing Measurable Measures Medicine Metabolism Modeling Morphology Movement Mus Muscle Muscle Contraction Mutation Myocardial dysfunction Neuromuscular Diseases Newborn Infant Palliative Care Pathology Patients Pharmaceutical Preparations Phase Phenotype Physiological Populations at Risk Pre-Clinical Model Preclinical Testing Proteins Recovery Recovery of Function Respiratory Failure Safety Scheme Skeletal Muscle Small Business Innovation Research Grant Source Speed System Testing Therapeutic Therapeutic Effect Time Tissue Model Tissue constructs Translating Translations Variant Western Blotting Work animal data biological systems canine model clinical trial in a dish comparative efficacy cost design disease phenotype drug development exon skipping experience gene therapy human data human disease human tissue improved in vitro Assay in vitro Model in vitro testing induced pluripotent stem cell male mdx mouse mosaic mouse model novel novel therapeutic intervention novel therapeutics organ on a chip patient population pre-clinical premature prevent response screening sildenafil single molecule skeletal muscle wasting social stem cells success transcriptome sequencing translational study

项目摘要

PROJECT DESCRIPTION Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disorder with no known cure that afflicts 1 in 5,000 newborn males. Patients carry a mutation in the dystrophin (DMD) gene, resulting in aberrant or absent expression of the dystrophin protein. Affected individuals experience progressive wasting of skeletal muscles and cardiac dysfunction leading to loss of ambulation and premature death, primarily due to cardiac or respiratory failure. Only palliative treatments are available, although gene therapy approaches for DMD have been effectively applied in dystrophic animal models by either directly targeting a class of mutations (as with exon skipping or gene editing) or by delivering a synthetic version of the dystrophin gene. The lack of scalable, human- based pre-clinical screening models is a significant roadblock to developing new therapies for these patients. Simple single molecule assays can be readily scaled, but lack the complexity needed to model muscle contraction which relies on a symphony of many biological systems working in concert to produce movement. At the other end of the spectrum, animal (particularly mouse) models have generated much that is known about the disease, but they are costly, slow, and in notable instances have given false positives for new treatments that failed to translate to humans. In this FastTrack SBIR proposal, Curi Bio and its partners will develop a novel preclinical screening platform for DMD that directly measures the contraction of stem cell-derived muscle tissue constructs from both human and murine cells. Because the contractility of tissue constructs is directly measured, therapies can be tested in the complex context of the mosaic of phenotypes that constitute muscle contraction. Further, the use of both murine and human cells will allow direct comparison of results to understand species- specific biology as well as to translate past results from animal models. Successful completion of this proposal will validate the platform’s ability to model contractile dysfunction in the dish, and to measure the degree of recovery after application of a novel therapeutic strategy that has been shown to restore the expression of healthy dystrophin in patient cells. The company will also leverage this platform by measuring the therapeutic effect of a revolutionary adeno-associated virus-based gene therapy that will be superior in both safety and efficacy compared to current approaches. The deliverables of this project will greatly improve the field’s ability to preclinically test novel therapeutics and will speed to market new lifesaving drugs for devastating diseases.

项目描述杜氏肌营养不良症 (DMD) 是一种致命的 X 连锁隐性遗传病，目前尚无已知的治愈方法，该病困扰着 1 5,000 名新生儿男性患者携带肌营养不良蛋白 (DMD) 基因突变，导致异常或缺失。受影响的个体会出现骨骼肌进行性萎缩。心脏功能障碍导致无法行走和过早死亡，主要是由于心脏或呼吸系统疾病虽然 DMD 的基因治疗方法已经出现，但只能采取姑息治疗。通过直接针对一类突变（如外显子跳过或基因编辑）或通过提供抗肌营养不良蛋白基因的合成版本。基于临床前筛选模型是为这些患者开发新疗法的重大障碍。简单的单分子测定可以很容易地扩展，但缺乏肌肉建模所需的复杂性收缩依赖于许多生物系统协同工作来产生运动。另一方面，动物（特别是小鼠）模型已经产生了许多关于疾病，但它们是昂贵的、缓慢的，而且值得注意的是，新疗法给出了假阳性结果，在这项 FastTrack SBIR 提案中，Curi Bio 及其合作伙伴将开发一种新颖的药物。直接测量干细胞来源的肌肉组织收缩的 DMD 临床前筛查平台由于组织结构的收缩性是直接测量的，可以在构成肌肉收缩的表型镶嵌的复杂背景下测试疗法。此外，使用小鼠和人类细胞将可以直接比较结果以了解物种- 特定生物学以及转化动物模型的过去结果成功完成了该提案。将验证该平台模拟培养皿中收缩功能障碍的能力，并测量收缩功能障碍的程度应用新的治疗策略后恢复，该策略已被证明可以恢复健康的表达该公司还将通过测量患者细胞中的肌营养不良蛋白的治疗效果来利用该平台。革命性的基于腺相关病毒的基因治疗，安全性和有效性均优越与目前的方法相比，该项目的可交付成果将大大提高该领域的能力。临床前测试了新的疗法，并将加速向市场推出治疗毁灭性疾病的新救生药物。