A Precision Medicine for Alcohol-Associated Liver Disease

酒精相关肝病的精准医学

• 批准号: 10748924
• 负责人: Charles Larry Bisgaier
• 金额: $ 97.67万
• 依托单位: GENETOBE INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748924
• 关键词: AODR mortality; Acetylgalactosamine; Alcohol consumption; Alcoholic Liver Diseases; Alleles; Amino Acids; Animals; Antisense Oligonucleotides; Cessation of life; Chemistry; Chronic; Clinical; Clinical Research; Clinical Trials; DNA; Data; Development; Diet; Disease; Dominant-Negative Mutation; Dose Limiting; Down-Regulation; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Ethanol; Etiology; Evaluation; FDA approved; Fatty Liver; Fibrosis; Formulation; Future; Genes; Genetic; Genetic Medicine; Genetic Polymorphism; Genetic Transcription; Goals; Good Manufacturing Process; Health; Hepatic; Hepatotoxicity; Histology; Human; Individual; Inflammation; Interruption; Investigation; Investigational Drugs; Investigational New Drug Application; Lead; Legal patent; Liver; Liver Fibrosis; Liver diseases; Malignant neoplasm of liver; Manufacturer; Medical; Messenger RNA; Metabolism; Modeling; Modification; Molecular; Monkeys; Mutation; Names; Oligonucleotides; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phenotype; Phospholipase; Plasma; Positioning Attribute; Precision therapeutics; Predisposition; Prevention; Protein Isoforms; Proteins; RNA Interference; Rattus; Research Contracts; Rodent; Role; Safety; Single Nucleotide Polymorphism; Small Interfering RNA; Specific qualifier value; Specificity; Testing; Therapeutic; Time; Toxic effect; Toxicology; Treatment-related toxicity; Triglyceride Metabolism; Variant; alcohol abuse therapy; comparative efficacy; design; disease phenotype; disorder subtype; drug candidate; drug development; first-in-human; genetic risk factor; genome wide association study; genotoxicity; good laboratory practice; human disease; human study; immunogenicity; improved; knock-down; liver injury; liver transplantation; manufacture; meetings; mortality; mouse model; mutant; nonalcoholic steatohepatitis; nonhuman primate; novel; novel therapeutics; overexpression; phase 1 study; phase 2 study; precision genetics; precision medicine; programs; prototype; quality assurance; safety testing; screening; small hairpin RNA; social; success; targeted treatment; therapeutic target; treatment strategy

ABSTRACT The goal of this study is to develop an RNAi-based genetic precision medicine to treat alcohol associated liver disease (AALD). AALD is a devastating health problem worldwide, accounts for the majority of alcohol-related mortality globally and is the second most indication for liver transplantation in the US. The current medical management for AALD remains limited, and no proven pathobiology-driven pharmacotherapy is available. There is thus an urgent need to identify novel targets and develop promising therapies for both prevention and treatment for AALD. Recent genome-wide association studies (GWAS) has identified that a single nucleotide polymorphism (SNP rs738409 C>G, or amino acid alteration at position 148 I>M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is the single largest genetic risk factor contributing to the progression of AALD to advanced liver perturbations including liver cancer. The PNPLA3 148 I>M polymorphism is the molecular reason why this subset of AALD patients develop severe liver injuries. Mechanistic studies have revealed that overexpression of the mutant PNPLA3 (the 148M isoform) is underlying both liver steatosis and fibrosis and inflammation by interrupting hepatic triglyceride metabolism. Our creation of a humanized PNPLA3148M mouse model successfully recapitulates the AALD phenotypes and has corroborated the aforementioned mechanism. We hypothesize that transcriptional downregulation of the PNPLA3148M isoform is a cause-targeting strategy for the treatment of AALD with the PNPLA3148M allele. To this end, we pioneered the development and have issued patents for a precision allele-specific small interfering RNA (siRNA) that possesses excellent specificity for the PNPLA3148M isoform compared to its wild-type counterpart. We further discovered two more modified oligonucleotides which significantly improved the medicinal chemistry specifications of our therapeutic lead. Administration of our lead siRNA to the liver of the humanized PNPLA3148M model fed an ethanol-containing diet significantly reduced the PNPLA3148M expression as well as hepatic steatosis, inflammation and fibrosis. We also demonstrated that delivering our siRNA into the humanized PNPLA3148M model with the N-Acetylgalactosamine (GalNAc)-conjugation, a well-established liver-specific drug delivery strategy, effectively knocked down hepatic hPNPLA3148M mRNA and ameliorated the liver histology. With this success, we propose to advance our drug candidate development by focusing on an Investigational New Drug (IND) application to the FDA. Specifically, we aim: 1) to define the best drug candidate of our hPNPLA3148M-targeting, GalNAc-conjugated oligonucleotides (Phase I); 2) to collect IND-enabling quality assurance and safety data in rodents and non-human primates (Phase II). We expect that via this study, we will develop the first genetic medicine for AALD treatment, which could also serve as a new prototype for drug development for other common human diseases. The collected data in this study will enable us to file the IND application to support our first clinical trial in humans.

摘要 本研究的目标是开发一种基于RNAi的遗传精密药物来治疗酒精相关性肝 疾病(AALD)。酒精性酒精性酒精症是世界范围内毁灭性的健康问题，占与酒精有关的大部分 全球范围内的死亡率，是美国肝移植的第二大适应症。当前的医学 急性酒精性肝病的治疗仍然有限，而且还没有得到证实的病理生物学驱动的药物治疗方法。那里 因此，迫切需要确定新的靶点并开发有前景的预防和治疗方法 为了AALD。最近的全基因组关联研究发现，单核苷酸多态 (SNP rs738409C&gt；G，或第148位氨基酸改变)位于Patatin样磷脂酶结构域 包含3(PNPLA3)基因是导致AALD进展到 包括肝癌在内的晚期肝脏疾病。PNPLA3148I&gM多态是其分子原因 为什么这个亚群的AALD患者会出现严重的肝脏损伤。机械论研究表明， 突变的PNPLA3(148M亚型)的过度表达是肝脏脂肪变性和纤维化的基础，并且 通过阻断肝脏甘油三酯代谢而引起的炎症。我们创造了一个人性化的PNPLA3148M小鼠 模型成功地概括了AALD的表型，并证实了上述机制。 我们假设PNPLA3148M亚型转录下调是一种原因靶向策略 PNPLA3148M等位基因治疗急性酒精性肝病为此，我们率先开发并发布了 获得一种精确的等位基因特异性小干扰RNA(SiRNA)的专利，该小干扰RNA具有良好的特异性 PNPLA3148M亚型与野生型的比较。我们进一步发现了另外两个经过修改的 寡核苷酸，显著提高了我们的治疗铅的药物化学规格。 含乙醇饲料人源化PNPLA3148M模型肝脏中铅siRNA的作用 显著降低PNPLA3148M的表达，减少肝脏脂肪变性、炎症和纤维化。我们也 证明了将我们的siRNA与N-乙酰半乳糖胺一起导入人源化PNPLA3148M模型 (GalNAc)-偶联，一种成熟的肝脏特异性药物传递策略，有效地击倒了肝脏 HPNPLA3148M m RNA，改善肝组织学改变。随着这一成功，我们计划推进我们的药物 通过专注于向FDA提交的研究性新药(IND)申请进行候选开发。具体来说， 我们的目标是：1)确定我们的hPNPLA3148M靶向GalNAc偶联寡核苷酸的最佳候选药物 (第一阶段)；2)收集在啮齿动物和非人类灵长类动物中启用IND的质量保证和安全数据 (第二阶段)。我们期待通过这项研究，开发出治疗AALD的第一种基因药物， 也可以作为治疗其他常见人类疾病的药物开发的新原型。收集到的 这项研究中的数据将使我们能够提交IND申请，以支持我们的第一次人体临床试验。