RNA-induced reprogramming of liver cells

• Applicant: Professor Amar Deep Sharma, Ph.D.
• Subject Area: Gastroenterology ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 462713102

Liver fibrosis and cirrhosis, common features of most chronic injuries including non-alcoholic steatohepatitis, alcoholic liver disease and viral infection, are considered unmet medical needs and are a significant health burden worldwide. Therefore, effective therapies for the treatment of liver fibrosis and cirrhosis are urgently needed. Profibrogenic myofibroblasts are key regulators of liver fibrosis. We have previously demonstrated that the de novo generation of hepatocytes from profibrogenic myofibroblasts through transcription factors (FOXA3, GATA4, HNF1A and HNF4A (4TF))-mediated cellular reprogramming attenuates liver fibrosis in mice. Our previous proof-of-principle study utilized targeted adenoviral delivery of 4TF. This approach, however, would raise safety concerns in patients with liver fibrosis due to high immunogenicity and host DNA interference of the adenoviral vector. This current proposal therefore aims to develop a safe and efficient in vivo hepatic reprogramming modality to treat patients with liver fibrosis. We have recently generated myo-targospheres, which are non-viral, fully metabolized nanoparticles, designed to deliver therapeutic payloads to mouse and human myofibroblasts of the liver. We will utilize myo-targospheres mediated delivery of RNA transiently expressing 4TF, for reprogramming profibrogenic myofibroblasts into hepatocytes, thereby avoiding viral delivery and genotoxic interference with host DNA. The research proposed in current proposal is a novel approach to achieve in vivo reprogramming of human myofibroblasts into hepatocytes by RNA. Further, this is a non-viral, non-DNA, non-integrating method, and would therefore make this approach clinically applicable for treatment of liver fibrosis. The development of the proposed innovative technologies will be an important milestone to translate liver targeted reprogramming-based therapy to attenuate hepatic fibrosis and cirrhosis in humans.

• DFG Programme: Research Grants