Clinically suitable approach for gene-mediated therapy of cirrhosis.

临床上适合基因介导的肝硬化治疗方法。

• 批准号: 8647959
• 负责人: Estuardo Aguilar-Cordova
• 金额: $ 22.5万
• 依托单位: ADVANTAGENE, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647959
• 关键词: Adenovirus Vector; Alcohol consumption; Attenuated; Biological Assay; Cause of Death; Cells; Certification; Cessation of life; Chronic; Cicatrix; Cirrhosis; Clinical; Clinical Pharmacology; Clinical Research; Collagen; DNA Sequence; Data; Deposition; Development; Disease; Dose; Enzymes; Equilibrium; Excision; Extracellular Matrix; Fatty Alcohols; Fatty Liver; Feedback; Fibrillar Collagen; Fibrosis; Gene Delivery; Gene Expression; Gene Transfer; Genes; Grant; Growth; Healed; Health; Hepatic; Hepatitis C virus; Hepatocyte; Human; Infection; Inflammation; Injury; Injury to Liver; Intervention; Laboratories; Lesion; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Mediating; Modeling; Molecular Cloning; Morphology; Natural regeneration; Patients; Phase; Pre-Clinical Model; Process; Production; Rattus; Resources; Safety; Source; Symptoms; Testing; Therapeutic Intervention; Tissues; Toxic effect; Translating; Translations; Validation; Viral; Virus; Work; Wound Healing; adeno-associated viral vector; age group; clinical toxicology; collagenase; design and construction; experience; good laboratory practice; healing; improved; injured; liver injury; mortality; pre-clinical; public health relevance; response; transgene expression; vector

Abstract Persistent injury to the liver can cause chronic inflammation and dysregulated deposition of extracellular matrix (ECM), leading to accumulation of fibrotic scar tissue and eventually cirrhosis. While fibrosis is a normal wound healing response, in excess, it can further injure tissue and activate pro-fibrotic cells, resulting in a positive feedback loop. Scar tissue is not static, ECM remodeling is a dynamic and regulated process that holds promise for targeted intervention of fibrotic disease. Furthermore, recent observations suggest the potential for the 'reversal' of advanced liver disease upon removal of the source of injury. In cirrhosis, aggressive removal of scar tissue would likely be needed to halt the positive feedback loop and create space for healthy hepatocyte growth. One hypothesis for achieving this is the introduction of ECM regulating enzymes, such as the collagenase Matrix Metalloprotienase-8 (MMP-8), thus shifting the balance of pro-fibrotic versus anti-fibrotic components, breaking the positive feedback loop that leads to further fibrotic deposits and creating space for healthy hepatocyte expansion. This approach led to marked decreases in fibrotic lesions, decreased hepatic collagen burden, improved gross liver morphology, and cirrhosis-associated symptoms in rat cirrhosis models. However, highly efficient adenoviral vectors were used for those proof-of-concept studies. Potential toxicity hinders the use of adenoviral vectors for liver transduction in humans. Thus, translation of these findings to human studies will require a more clinically suitable approach, while maintaining efficient gene delivery. This application proposes the design, construction, manufacture, and characterization of an Adeno-associated viral (AAV) vector expressing MMP-8 to accomplish this and advanced this project to clinical studies. The collaborative team included in this proposal has extensive experience with GMP-AAV manufacturing, preclinical models for fibrotic disease, and has the regulatory and clinical development expertise required to translate the results into a human gene transfer study in patients with cirrhosis. Upon successful completion of this proposal, the second phase of this project will include GMP vector production and pre-clinical pharmacology and toxicology studies necessary to submit an IND to support clinical studies.

摘要