Evaluation of Novel Cyclophilin D Inhibitors for Mitochondrial Disease Therapy

描述（由申请人提供）：由线粒体呼吸链遗传异常引起的肌病和其他临床疾病总共影响多达8000人中有1人，总体上代表了重大的疾病负担，尽管特定的潜在遗传病变非常罕见。尽管需要治疗策略来预防或减缓这些经常致残和有时致命的遗传疾病的进展，但线粒体疾病患者的现有治疗选择主要局限于症状管理。遗传和临床异质性使得这些疾病的诊断、治疗和治疗发现具有挑战性，并且对大多数线粒体疾病的疾病修饰治疗仍然难以捉摸。抑制多种线粒体疾病共同的特定细胞病理可以补充针对个体疾病的原发性遗传缺陷的方法，并有助于减少疾病进展的联合策略。线粒体功能障碍的一个后果是线粒体内膜的通透性增加，这是通过线粒体通透性过渡孔（MPTP）的多蛋白通道打开造成的。MPTP调节剂亲环蛋白D的药理学抑制剂，如免疫抑制剂环孢素A，可以减少线粒体疾病患者培养细胞中线粒体功能障碍引起的细胞病理。这些观察结果表明，抑制亲环蛋白D可能是减轻疾病相关线粒体功能障碍影响的有效策略。在初步研究中，SCYNEXIS已经确定了两种非免疫抑制的亲环蛋白D抑制剂，它们可以阻断MPTP的开放，并在急性线粒体应激的体内模型中有效地保护心肌。这个I期SBIR项目的主要目标是测试这些亲环蛋白D抑制剂减轻慢性线粒体功能障碍引起的细胞表型的能力。通过这些新的亲环蛋白D抑制剂，线粒体突变细胞中的细胞疾病表型将被证明是合理的。我们还将介绍化合物和较新的类似物的选择特性，有利于用于慢性治疗给药。这些结果将为II期的先导物发现和优化计划的设计提供信息，其长期目标是确定一种或多种线粒体疾病的临床前治疗候选药物。

DESCRIPTION (provided by applicant): Myopathies and other clinical disorders arising from genetic abnormalities of the mitochondrial respiratory chain collectively affect as many as 1 in 8000 individuals, representing in aggregate a significant disease burden, even though the specific underlying genetic lesions are each quite rare. Despite the need for therapeutic strategies to prevent or slow the progression of these often disabling and at times fatal genetic diseases, existing treatment options for mitochondrial disease patients are limited primarily to symptom management. Genetic and clinical heterogeneity make diagnosis, treatment, and therapeutic discovery for these diseases challenging, and disease-modifying treatments remain elusive for the majority of mitochondrial disorders. Inhibition of specific cellular pathology common to multiple mitochondrial diseases could complement approaches targeting the primary genetic defects in individual disorders, and contribute to combination strategies for reducing disease progression. One consequence of mitochondrial dysfunction can be increased permeability of the inner mitochondrial membrane, via opening of a multiprotein channel known as the mitochondrial permeability transition pore (MPTP). Pharmacologic inhibitors of the MPTP modulator cyclophilin D, such as the immunosuppressant cyclosporine A, can reduce the cellular pathology arising from mitochondrial dysfunction in cultured cells derived from mitochondrial disease patients. These observations suggest that cyclophilin D inhibition could be a valid strategy for attenuating the effects of disease-associated mitochondrial dysfunctions. In preliminary studies, SCYNEXIS has identified two non-immunosuppressive cyclophilin D inhibitors that block MPTP opening and are efficacious in protecting cardiac muscle in an in vivo model of acute mitochondrial stress. The key objective of this Phase I SBIR project is to test the ability of these cyclophilin D inhibitors to attenuate cellular phenotypes resulting from chronic mitochondrial dysfunction. Progression to a Phase II project will be justified by attenuation of cellular disease phenotypes in mitochondrial mutant cells by these novel cyclophilin D inhibitors. We will also profile the compounds and newer analogs for selected properties favorable for use in chronic therapeutic administration. The results will inform the design of a full lead discovery and optimization program to be pursued in Phase II, with the long-term goal of identifying a preclinical therapeutic candidate for one or more mitochondrial diseases.