Characterization of small molecules that lower mutant huntingtin protein as potential therapeutics for Huntington’s disease

降低突变亨廷顿蛋白作为亨廷顿病潜在疗法的小分子的表征

• 批准号: 10759097
• 负责人: Beth J Hoffman
• 金额: $ 50.29万
• 依托单位: ORIGAMI THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10759097
• 关键词: ABCB1 gene; ADME Study; Animal Model; Area; Aspiration Pneumonia; Atrophic; Autophagocytosis; Binding Proteins; Biological Assay; Biological Availability; Blood; Blood Tests; Brain; CAG repeat; Cell Death; Cell Differentiation process; Cell division; Cell physiology; Cells; Cerebral cortex; Cerebrospinal Fluid; Chemicals; Clinical; Clinical Trials; Cognitive deficits; Corpus striatum structure; Cystic Fibrosis; DNA Damage; Development; Disease; Disease Progression; Dose; Drug Compounding; Drug Kinetics; Excretory function; Family; Fibroblasts; Functional disorder; Gene Proteins; Genes; Genetic; Genetic Transcription; Glutamine; Grant; Heart Diseases; Histopathology; Human; Huntington Disease; Huntington gene; In Vitro; Individual; Inherited; Intravenous; Investigational New Drug Application; Lead; Legal patent; Length; Liver Microsomes; Mass Spectrum Analysis; Measures; Medical; Metabolism; Mitochondria; Modality; Morbidity - disease rate; Motor; Mus; Mutation; N-terminal; Neurites; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Operative Surgical Procedures; Oral; Oral Administration; Organ; Pathway interactions; Patients; Penetration; Peripheral; Persons; Pharmaceutical Preparations; Phase; Physiology; Plasma Proteins; Post-Translational Protein Processing; Predisposition; Prevalence; Procedures; Prognosis; Property; Proteins; Rest; Safety; Signal Transduction; Skeletal Muscle; Small Business Innovation Research Grant; Solubility; Stretching; Symptoms; Synaptic Transmission; System; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Toxic effect; absorption; analog; autosome; clinical translation; commercialization; curative treatments; design; drug candidate; effective therapy; efficacy evaluation; efficacy testing; falls; gain of function; gene discovery; in vivo; in vivo evaluation; induced pluripotent stem cell; innovation; insight; mortality; mouse model; mutant; nervous system disorder; neuron loss; neuroprotection; novel therapeutic intervention; pharmacokinetics and pharmacodynamics; polyglutamine; potential biomarker; pre-clinical; prevent; programs; research clinical testing; response; safety assessment; safety study; scaffold; screening; small molecule; therapeutic target

SUMMARY Huntington’s disease (HD) is an autosomal dominant, progressive and fatal neurodegenerative disease that effects 200,000 people worldwide. Despite discovery of the gene more than 25 years ago and more than 150 clinical trials, there is still no effective treatment for HD. The development of any therapy that slows, halts, or prevents disease would have a major impact on the patients and their families. HD is caused by the expansion of a CAG repeat in the huntingtin gene (HTT), resulting in an expanded stretch of glutamines in the huntingtin protein. Normal huntingtin protein (HTT) is essential throughout the body and brain to regulate cell physiology including synaptic transmission and neuroprotection, cell division and differentiation, gene transcription and the DNA damage response. In patients with HD, the expanded polyglutamine tract causes mutant HTT (mHTT) to fold abnormally, resulting in aberrant post-translational modifications and cleavage to generate toxic mHTT fragments. The N-terminal mHTT fragments form oligomers that interact with many cellular proteins, disrupting cell function, resulting in increased levels of mHTT and causing mHTT inclusions. Substantial neuronal dysfunction and death occur in striatal medium spiny neurons (MSNs) and the cerebral cortex. Experimental procedures that lower mHTT have reversed disease symptoms in animal models of HD. However, clinical translation of this mechanism of action has stalled and is, in part, hypothesized to be due to nonselective lowering of both the essential HTT as well as mHTT. In addition, some of the drug candidates in clinical trials target the brain exclusively, use therapeutic modalities that require invasive delivery systems and leave the rest of the body untreated. Therefore, an orally delivered, systemically distributed, brain-penetrant therapeutic that selectively eliminates toxic mHTT while sparing the functional forms of HTT to support normal physiology could offer an effective treatment for all HD patients. By applying its expertise in screening, Origami Therapeutics (OT) has identified a chemical scaffold, represented by OR1-113, that prevents mHTT aggregation, and selectively lowers mHTT levels in cell-based assays by enhancing degradation through an autophagy pathway as demonstrated in HD patient-derived fibroblasts, human HD iPSC-derived medium spiny neurons and in vivo in the cortex and striatum of the YAC128 mouse model of HD. Twelve analogues of ORI-113 have been designed. The efficacy and drug-like properties of OR1-113 and 12 analogues will be compared in HD patient iPSC-derived MSNs and in vitro absorption, distribution, metabolism, and excretion studies will provide insight regarding the metabolism and potential interactions of the drug compounds (Aim 1). Pharmacokinetic (PK) and brain exposure profiles of four lead compounds selected from Aim 1 will be determined in mice for oral availability (Aim 2). The top two ranked leads will be evaluated in a combined PK/Pharmacodynamic and safety study in YAC128 mice with oral administration (Aim 3). These studies will identify a lead therapeutic drug candidate that will move into Investigational New Drug Application studies that are required prior to initiation of clinical testing.

总结 亨廷顿氏病（HD）是一种常染色体显性遗传的、进行性的和致命的神经退行性疾病， 影响了全世界20万人尽管该基因在25年前就被发现， 在临床试验中，仍然没有有效的治疗HD的方法。任何减缓、停止或 预防疾病将对患者及其家庭产生重大影响。HD是由膨胀引起的 亨廷顿蛋白基因（HTT）中CAG重复序列的缺失，导致亨廷顿蛋白中谷氨酰胺的延伸 蛋白正常的亨廷顿蛋白（HTT）在整个身体和大脑中是必不可少的，以调节细胞生理学 包括突触传递和神经保护，细胞分裂和分化，基因转录和 DNA损伤反应。在HD患者中，扩展的多聚谷氨酰胺束导致突变型HTT（mHTT）， 折叠异常，导致异常翻译后修饰和切割，产生毒性mHTT 片段N-末端mHTT片段形成与许多细胞蛋白相互作用的寡聚体， 细胞功能，导致mHTT水平增加并引起mHTT包涵体。实质性神经元 功能障碍和死亡发生在纹状体中型多刺神经元（MSN）和大脑皮层中。实验 降低mHTT的程序在HD动物模型中逆转了疾病症状。但临床 这种作用机制的翻译已经停滞，部分假设是由于非选择性降低 基本的HTT和mHTT。此外，临床试验中的一些候选药物靶向 专门用于大脑，使用需要侵入性输送系统的治疗方式， 未经治疗。因此，口服递送的全身分布的脑渗透治疗剂选择性地 消除有毒的mHTT，同时保留HTT的功能形式以支持正常的生理机能， 所有HD患者的有效治疗。通过应用其在筛选方面的专业知识，折纸治疗（OT） 鉴定了一种化学支架，以OR 1 -113为代表，可防止mHTT聚集，并选择性降低 通过自噬途径增强降解，在基于细胞的测定中提高mHTT水平， 在HD患者来源的成纤维细胞、人HD iPSC来源的中等多刺神经元和体内皮质中， HD的YAC 128小鼠模型的纹状体。已经设计了12种ORI-113类似物。疗效 将在HD患者iPSC衍生的MSN中比较OR 1 -113和12类似物的药物样性质， 体外吸收、分布、代谢和排泄研究将提供关于代谢的见解 和药物化合物的潜在相互作用（目的1）。以下药物的药代动力学（PK）和脑暴露特征 将在小鼠中测定选自目标1的四种先导化合物的口服利用度（目标2）。前两名 将在YAC 128小鼠中进行的PK/药效学和安全性联合研究中评价经口给药 目标3）。这些研究将确定一种领先的治疗药物候选药物，该药物将进入 在开始临床试验之前需要进行的新药申请研究。