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 本研究的目的是开发一种基于RNAi的基因精准医学来治疗酒精相关性肝脏 疾病（AALD）。AALD是一个毁灭性的全球性健康问题，占大多数与酒精有关的 在全球范围内死亡率最高，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，并且没有经过证实的病理生物学驱动的药物疗法可用。那里 因此，迫切需要确定新的靶点并开发有希望的预防和治疗方法 对于AALD。最近的全基因组关联研究（GWAS）已经确定，单核苷酸多态性 (SNP rs738409 C>G，或位置148 I>M处的氨基酸改变） PNPLA 3基因是导致AALD进展为 包括肝癌在内的晚期肝脏扰动。PNPLA 3 148 I>M多态性是导致其发生的分子原因 为什么这部分AALD患者会发生严重的肝损伤。机制研究表明， 突变PNPLA 3（148 M同种型）的过表达是肝脂肪变性和纤维化的基础， 通过中断肝脏甘油三酯代谢来治疗炎症。我们创建人源化PNPLA 3148 M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PNPLA 3148 M亚型的转录下调是一种病因靶向策略， 用PNPLA 3148 M等位基因治疗AALD。为此，我们率先开发并发行了 专利的精确等位基因特异性小干扰RNA（siRNA），具有优异的特异性， PNPLA 3148 M同种型与其野生型对应物相比。我们还发现了另外两个 这些寡核苷酸显著改善了我们的治疗先导药物的药物化学规格。 将我们的前导siRNA施用至喂食含乙醇饮食的人源化PNPLA 3148 M模型的肝脏 显著降低PNPLA 3148 M表达以及肝脂肪变性、炎症和纤维化。我们也 证明了将我们的siRNA递送到具有N-乙酰半乳糖胺的人源化PNPLA 3148 M模型中， （GalNAc）-缀合，一种成熟的肝脏特异性药物递送策略，有效地敲低了肝细胞的表达。 hPNPLA 3148 M mRNA的表达，并改善肝组织学。有了这个成功，我们建议将我们的药物 通过专注于向FDA提交研究性新药（IND）申请来开发候选药物。具体地说， 我们的目标是：1）确定我们的hPNPLA 3148 M靶向的GalNAc缀合的寡核苷酸的最佳候选药物 （I期）; 2）收集啮齿动物和非人灵长类动物的IND质量保证和安全性数据 （第二阶段）。我们希望通过这项研究，我们将开发出第一种用于AALD治疗的遗传药物， 也可以作为其他常见人类疾病药物开发的新原型。所收集的 这项研究中的数据将使我们能够提交IND申请，以支持我们的第一个人体临床试验。