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.

概括 亨廷顿病 (HD) 是一种常染色体显性遗传、进行性、致命性神经退行性疾病， 尽管该基因在 25 多年前就被发现，并且影响了全世界 150 多人。 临床试验中，目前还没有任何能够减缓、停止或阻止 HD 的有效治疗方法。 预防疾病的扩大会对患者及其家人造成重大影响。 亨廷顿基因 (HTT) 中的 CAG 重复序列，导致亨廷顿蛋白中谷氨酰胺的延伸 正常亨廷顿蛋白 (HTT) 在整个身体和大脑中对于调节细胞生理学至关重要。 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会导致突变 HTT (mHTT) 折叠异常，导致异常的翻译后修饰和裂解产生有毒的 mHTT N 端 mHTT 片段形成寡聚体，与许多细胞蛋白相互作用，从而破坏细胞。 细胞功能，导致 mHTT 水平增加并导致大量神经元包涵体。 纹状体中棘神经元（MSN）和实验大脑皮层发生功能障碍和死亡。 降低 mHTT 的方法可以逆转 HD 动物模型中的疾病症状。 这种作用机制的转化已经停滞，部分原因是非选择性降低 此外，临床试验中的一些候选药物还针对基本 HTT 和 mHTT。 大脑，使用需要侵入性输送系统的治疗方式，而只留下身体的其他部位 因此，一种口服、全身分布、选择性的脑渗透疗法。 消除有毒的 mHTT，同时保留 HTT 的功能形式以支持正常生理机能可以提供 通过运用其筛查方面的专业知识，Origami Therapeutics (OT) 已经为所有 HD 患者提供了有效的治疗。 确定了一种以 OR1-113 为代表的化学支架，它可以防止 mHTT 聚集，并选择性地降低 通过自噬途径增强降解，以细胞为基础的检测中的 mHTT 水平 在 HD 患者来源的成纤维细胞、人 HD iPSC 来源的中型多棘神经元以及体内皮质和 已设计了 HD 的 YAC128 小鼠模型的纹状体中的 12 种 ORI-113 类似物。 OR1-113 和 12 类似物的药物特性将在 HD 患者 iPSC 衍生的 MSN 中进行比较 体外吸收、分布、代谢和排泄研究将提供有关代谢的见解 以及药物化合物的潜在相互作用（目标 1）和脑暴露曲线。 从目标 1 中选择的四种先导化合物将在小鼠中进行口服利用度测定（目标 2）。 排名领先的药物将在 YAC128 小鼠中进行联合 PK/药效学和安全性研究中进行评估 这些研究将确定将进入的主要治疗药物候选者。 在开始临床测试之前需要进行研究性新药应用研究。