Ex Vivo Base Editing Therapy with Chemically Derived Hepatic Progenitors

Area of Science:

• Biotechnology
• Genetics
• Hepatology

Background:

• Ex vivo gene therapy is a developing field for treating intractable genetic diseases.
• Small molecules can reprogram mature hepatocytes into bipotent hepatic progenitors.
• Base and prime editors offer precise gene editing capabilities.

Purpose of the Study:

• To establish a protocol for ex vivo gene therapy using base/prime editors.
• To generate and select gene-corrected hepatic progenitors from hepatocytes.
• To evaluate the therapeutic potential in an inborn error of metabolism mouse model.

Main Methods:

• Terminally differentiated hepatocytes were reprogrammed into hepatic progenitors using small molecules.
• Base or prime editors were delivered into the generated hepatic progenitors.
• Corrected hepatic progenitors were selected and characterized.
• Transplantation of corrected cells into mice with inborn errors of metabolism.

Main Results:

• Successful generation of hepatic progenitors from hepatocytes.
• Efficient delivery and editing of target genes using base/prime editors.
• Selection of genetically corrected hepatic progenitor cells.
• Demonstration of engraftment and potential therapeutic effect in a disease model.

Conclusions:

• Ex vivo gene therapy combining cell reprogramming and advanced gene editing is feasible.
• This approach holds promise for treating hereditary metabolic diseases.
• Further studies are warranted to optimize and translate this strategy.