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

• 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
• 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

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连锁隐性疾病，没有已知的治疗，折磨1 在5,000个新生的雄性中。患者携带肌营养不良蛋白（DMD）基因突变，导致异常或缺失 抗肌萎缩蛋白的表达。受影响的个体经历骨骼肌的进行性消耗 和心脏功能障碍，导致心律失常和过早死亡，主要是由于心脏或呼吸系统疾病， 失败只有姑息治疗是可用的，尽管DMD的基因治疗方法已经被证明是有效的。 通过直接靶向一类突变（如外显子 跳跃或基因编辑）或通过递送合成形式的肌营养不良蛋白基因。缺乏可扩展的，人性化的 基于临床前筛选模型的研究是为这些患者开发新疗法的重要障碍。 简单的单分子测定可以容易地缩放，但缺乏模拟肌肉所需的复杂性 收缩依赖于许多生物系统协同工作产生运动的交响乐。在 另一方面，动物（特别是小鼠）模型已经产生了许多关于 疾病，但他们是昂贵的，缓慢的，并在显着的情况下，给假阳性的新治疗， 无法翻译给人类在这个FastTrack SBIR提案中，Curi Bio及其合作伙伴将开发一种新颖的 DMD的临床前筛选平台，可直接测量干细胞来源的肌肉组织的收缩 从人和鼠细胞构建。因为组织构建体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治疗。 此外，使用鼠细胞和人细胞将允许直接比较结果以了解物种。 具体的生物学以及翻译过去的结果从动物模型。成功完成本提案 将验证该平台在培养皿中模拟收缩功能障碍的能力，并测量 应用新的治疗策略后的恢复，该治疗策略已被证明可以恢复健康的 患者细胞中的肌营养不良蛋白。该公司还将利用这一平台，通过测量治疗效果， 一种革命性的基于腺相关病毒的基因疗法，在安全性和有效性方面都将是上级的 与目前的方法相比。该项目的成果将大大提高外地的能力， 临床前试验新的疗法，并将加速销售新的拯救生命的药物，用于毁灭性的疾病。