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.

抽象的 这项研究的目的是开发一种基于RNAi的遗传精度药物来治疗酒精相关的肝脏 疾病（AALD）。 AALD在全球范围内是毁灭性的健康问题，占与酒精有关的大多数 全球死亡率是美国肝移植的第二大迹象。当前的医疗 AALD的管理仍然有限，没有可靠的病理学驱动的药物治疗。那里 因此，迫切需要识别新的目标并开发有希望的预防和治疗疗法 为Aald。最近全基因组关联研究（GWAS）已经确定了单个核苷酸多态性 （SNP RS738409 C> G，或位置148 I> m处的氨基酸改变） 包含3（PNPLA3）基因是导致AALD发展的最大遗传危险因素 晚期肝扰动，包括肝癌。 PNPLA3 148 i> m多态性是分子原因 为什么这部分AALD患者会出现严重的肝损伤。机械研究表明 突变体PNPLA3（148M同工型）的过表达是肝脏脂肪变性和纤维化和 通过中断肝甘油三酸酯代谢而发炎。我们创建人源化PNPLA3148M鼠标 模型成功地概括了AALD表型，并证实了上述机制。 我们假设PNPLA3148M同工型的转录下调是针对性的策略 用PNPLA3148M等位基因处理AALD。为此，我们开创了开发项目，并已发布 专利具有精度等位基因特异性小干扰RNA（siRNA），具有极好的特异性 与其野生型对应物相比，PNPLA3148M同工型。我们进一步发现了两个修改 寡核苷酸可显着改善我们治疗铅的药物化学规范。 给予人源化PNPLA3148M模型的铅siRNA喂养含有乙醇的饮食 显着降低了PNPLA3148M表达以及肝脏脂肪变性，炎症和纤维化。我们也是 证明将我们的siRNA用N-乙酰乳糖胺将siRNA传递到人源化的PNPLA3148M模型中 （GALNAC） - 缀合是一种良好的肝脏特异性药物输送策略，有效地击倒了肝 HPNPLA3148M mRNA并改善肝组织学。有了这一成功，我们建议推进我们的毒品 候选人开发通过专注于FDA的研究新药（IND）申请。具体来说， 我们的目标：1）定义我们的HPNPLA3148M靶向Galnac偶联的寡核苷酸的最佳药物候选者 （第一阶段）; 2）收集啮齿动物和非人类灵长类动物的质量保证和安全数据 （第二阶段）。我们希望通过这项研究，我们将开发第一种用于AALD治疗的遗传医学，这是 还可以作为其他常见人类疾病的药物开发的新原型。收集的 这项研究中的数据将使我们能够提交IND应用程序，以支持我们在人类的第一次临床试验。