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S3-E17.1 – Potential Breakthrough in Anti-Fibrotic Therapies Through mRNA/CAR-T Combined Therapies

Scott Friedman discusses that background for the potential breakthrough work from Jon Epstein at the University of Pennsylvania on how combined mRNA/CAR-T therapy can regress fibrosis in mouse CVD models.

https://www.nature.com/articles/s41586-020-2403-9

Professors Scott Friedman and Neil Henderson join the Surfers (including the returning Stephen Harrison) to discuss some truly exciting advances in the basic science and technology of defining, diagnosing, and treating NAFLD and NASH. This conversation focuses largely on mRNA/CAR-T anti-fibrotic therapies.

Scott Friedman starts this conversation by reviewing the historical sequence that led to the development of an mRNA vaccine that can create CAR-T cells in mice for the express purpose of attacking fibrotic tissue.

Originally, CAR-T was developed to create cells that kill certain lymphomas. In the original design, white cells were extracted from the patient’s body and modified via DNA to include a special type of receptor on the cell. This receptor can target tumor cells and destroy them. Late in the last decade, researchers at Memorial Sloan Kettering in New York and the University of Pennsylvania published work demonstrating that when appropriately modified, CAR-T cells could destroy fibrogenic cells in mouse models, both in the liver (MSK) and the heart (UPenn).

Two challenges with current CAR-T therapy is that cells must be removed from the patient’s body to create the CAR-T cells (costly and carrying some risk) and that the original genetic material has been found in some patients’ bodies as long as a decade after therapy. A third challenge revolves around the high percentages of patients (12-20%) exhibiting Level 3 or higher Cytokine Response Syndrome (CRS) as an effect of therapy.

The UPenn group addressed the first two of these challenges by adapting mRNA technology (which underlies the Pfizer/BioNTech and Moderna COVID-19 vaccines) to modify white cells in the body to attack fibrogenic cells in the heart, with a similar effect to the externally generated cells. This addresses the first challenge because you can take “off the shelf” mRNA proteins and inject them into any patient’s body and expect highly consistent results (similar to the COVID-19 vaccine). It addresses the second challenge because mRNA is a protein packet that, after completing its work, dissolves into the body and is excreted.

While there are still many vital questions to be answered (CRS issues and transferability from mouse models to humans, to name two), this technology can provide a uniquely powerful way to regress late-stage NASH fibrosis and cirrhosis.

Before this conversation ends, I raise the point about the impact on CRS (no answer at this time) and Jörn Schattenberg asks Neil Henderson which cell type and receptor this therapy should address (and whether there is more than one). This question arises in the next discussion.

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