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.

项目说明 Duchenne肌营养不良症(DMD)是一种致命性、X连锁的隐性疾病，目前尚无治疗方法 在5000名刚出生的男性中。患者携带营养不良蛋白(DMD)基因突变，导致异常或缺失 抗肌营养不良蛋白的表达。受影响的人会经历骨骼肌的进行性萎缩 和心脏功能障碍，主要由心脏或呼吸系统引起，导致不能行走和过早死亡 失败了。目前只有姑息疗法可用，尽管基因治疗DMD的方法一直存在 通过直接针对一类突变(如外显子)有效地应用于营养不良动物模型 跳过或基因编辑)或通过传递抗肌营养不良蛋白基因的合成版本。缺乏可扩展的、人性化的- 基于临床前筛查模型是为这些患者开发新疗法的重要障碍。 简单的单分子分析可以很容易地扩展，但缺乏对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的交响乐来产生运动。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，但它们昂贵、缓慢，在值得注意的情况下，对新的治疗方法给出了假阳性， 未能将其转化为人类。在这份FastTrack SBIR提案中，Curi Bio及其合作伙伴将开发一种新的 直接测量干细胞源性肌肉组织收缩的DMD临床前筛查平台 由人类和小鼠细胞构建而成。因为直接测量组织构造物的收缩性， 治疗方法可以在构成肌肉收缩的表型马赛克的复杂背景下进行测试。 此外，使用小鼠和人类细胞将允许直接比较结果，以了解物种- 并将过去的研究结果转化为动物模型。成功完成本建议书 将验证平台模拟碟状肌收缩功能障碍的能力，并测量 在应用一种新的治疗策略后恢复，该策略已被证明恢复了健康的表达 患者细胞中的抗肌营养不良蛋白。该公司还将利用这一平台，通过测量 革命性的基于腺相关病毒的基因治疗将在安全性和有效性方面都更胜一筹 与目前的方法相比。该项目的交付成果将极大地提高外地的能力 临床前测试新的治疗方法，并将加快推出治疗毁灭性疾病的新的救命药物。