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.
Cirrhosis is a deadly disease caused by scarring of the liver most often due to extended inflammation from infections, fatty liver or alcohol consumption. The scar tissue blocks normal liver cell regeneration and further stimulates inflammation. Thus, removal of the scar tissue appears to be a promising way to allow the liver to heal and improve patient health. The work in this Phase 1 proposal include the manufacture a virus with a cargo to remove these scars, and to perform laboratory testing required to initiate clinical studies.