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 本研究的目标是开发一种基于 RNAi 的基因精准药物来治疗酒精相关性肝病 疾病（AALD）。 AALD 是世界范围内一种毁灭性的健康问题，大部分与酒精有关 全球死亡率最高，是美国肝移植的第二大适应症。目前的医疗 AALD 的管理仍然有限，并且没有经过验证的病理生物学驱动的药物治疗。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疗法 对于 AALD。最近的全基因组关联研究（GWAS）发现单核苷酸多态性 patatin 样磷脂酶结构域中的（SNP rs738409 C>G，或位置 148 I>M 的氨基酸改变） 含有 3 (PNPLA3) 基因是导致 AALD 进展为单一最大的遗传风险因素 晚期肝脏紊乱，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。机理研究表明 突变体 PNPLA3（148M 同工型）的过度表达是肝脏脂肪变性和纤维化的基础 通过干扰肝脏甘油三酯代谢而产生炎症。我们创造了人性化 PNPLA3148M 小鼠 模型成功地概括了 AALD 表型并证实了上述机制。 我们假设 PNPLA3148M 亚型的转录下调是一种针对病因的策略 使用 PNPLA3148M 等位基因治疗 AALD。为此，我们率先开发并发布了 精密等位基因特异性小干扰 RNA (siRNA) 的专利，该技术对 PNPLA3148M 同工型与其野生型对应物相比。我们进一步发现了另外两个修改过的 寡核苷酸显着提高了我们治疗先导药物的药物化学规格。 将我们的先导 siRNA 注射到喂食含乙醇饮食的人源化 PNPLA3148M 模型的肝脏中 显着降低 PNPLA3148M 表达以及肝脏脂肪变性、炎症和纤维化。我们也 证明使用 N-乙酰半乳糖胺将我们的 siRNA 递送至人源化 PNPLA3148M 模型中 (GalNAc)-缀合是一种成熟的肝脏特异性药物递送策略，可有效抑制肝脏 hPNPLA3148M mRNA 并改善肝脏组织学。凭借这一成功，我们建议推进我们的药物 通过专注于向 FDA 提交研究性新药 (IND) 申请来开发候选药物。具体来说， 我们的目标：1) 确定我们的 hPNPLA3148M 靶向、GalNAc 缀合寡核苷酸的最佳候选药物 （第一阶段）； 2) 收集啮齿动物和非人类灵长类动物中支持 IND 的质量保证和安全数据 （第二阶段）。我们期望通过这项研究，我们将开发出第一种用于治疗 AALD 的基因药物， 还可以作为其他人类常见疾病药物开发的新原型。收集到的 这项研究中的数据将使我们能够提交 IND 申请，以支持我们的首次人体临床试验。