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S3-E17 – New In NASH Science: CAR-T/mRNA Anti-Fibrotics and Advanced NASH omics

What do recent findings in mRNA/CAR-T anti-fibrotic therapies and advanced NASH omics promise for the future of treating NAFLD and NASH?

CAR T cells produced in vivo to treat cardiac injury

Senolytic CAR T cells reverse senescence-associated pathologies

Professors Scott Friedman and Neil Henderson join the Surfers (including the returning Stephen Harrison) to discuss some truly exciting advances in advanced NASH omics, including work on mRNA/CAR-T anti-fibrotic therapies.

There is not enough room to capture this entire conversation in a summary. It’s a lot, but really eye-opening and exciting. Take the time to listen to the entire episode, even if in bite-sized pieces.

This episode starts with bonhomie and humor as the group congratulates Professor Friedman on being honored with a Lifetime Achievement Award from the faculty at Mt. Sinai and then listens as Professor Henderson relates one of the truly unique “one thing you wouldn’t know about me if I didn’t tell you” in the history of the podcast.

The science portion of the podcast starts with Scott discussing a fantastic series of advances in basic science wherein researchers have begun to evaluate CAR-T therapy, which was originally developed to treat lymphomas and other blood dyscrasias, to attack the surfaces of fibrogenic cells in the liver (MSK, New York) or, separately, the heart (University of Penn). Today, we create CAR-T cells by taking cells from the diseased patient, re-engineering them and injecting them back into the patient. This approach is associated with high rates of Level 3+ cytokine response syndrome (CRS). It has also been found to leave this engineered CAR-T material in the patient’s system at least a decade after therapy.

Scott goes on to explain how the Epstein lab at Penn integrated the CAR-T strategy with mRNA, the protein behind the Pfizer/BioNTech and Moderna DOVD-19 vaccines to create a vaccine that can reprogram cells within the body to replicate the CAR-T effect. Scott notes that so far, this has only been reported in mouse models and that there are many major issues to resolve before we know it will be safe and effective in humans. It is a staggering breakthrough nonetheless.

After a couple of questions, the group turns to Neil, who points out that this kind of finding can help “make precision medicine a reality,” in part because it creates the possibility we can target multimodal therapy at the exact target we want. Stephen suggests that the ideal place for this kind of therapy might be a late-stage patient where we can regress fibrosis and, once the liver is better able to function, resort to a more metabolic therapy.

Scott suggests how helpful it would be to develop insight into how different types of cells respond to different medications, which shifts the conversation shifts toward the broader topic of single-cell genomics, and specifically the growing utility of spatial transcriptomics in these situations. Neil provides a description of the benefits of spatial transcriptomics and then takes the group back through a history of omic technology.

Jörn Schattenberg asks what these techniques have taught us about the variability between patients. Neil discusses the congruence of individual samples. Jörn points out this would mean that we can develop robust therapies targeted at a cell type. Scott suggests that we can use these insights to standardize clinical trials to target the specific patients with the genetic targets most likely to respond — a large step on the path to personalized precision therapy.

In response to a question from Louise Campbell about sources for liver tissue, Neil asks for study purposes, “What is a normal human liver?” One of his major sources of tissue are distal liver sites from patients with colorectal cancer. However, even if these are cancer-free, thy could be affected by chemotherapy.

As the discussion winds down, the group comes to focus on the issue of why and how the liver regenerates. It raises fascinating questions: why does it not seem to “over-regenerate?” Are the regenerated cells different from pre-injury cells, and if so, how?

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