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S3-E17.2 – Future Targeted NASH Therapies and NASH Drug Development Today

What are the implications of the targeted NASH therapies of the future on NASH drug development today?

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 the implications of potentially exciting future technologies such as the mRNA/CAR-T therapy described in Conversation 17.1 on NASH drug development today.

After the earlier discussion of the potential future mRNA/CAR-T therapy, Scott Friedman turns to Neil Henderson and asks this question: “What cell type and what receptors on those cells do you hone in on, or do you do more than one? And how do you use single-cell genomics to help you sort through that complex question?”

Neil immediately connects the question and the technology to the need for precision medicine in NASH. He points out that one challenge with NASH is hitting a single target is always challenging, particularly when the target is as “evolutionarily conserved” as fibrosis. To Neil, this suggests that if the mRNA/CAR-T therapy comes to fruition, it will become one element — an important one, but not the only one — in what he describes as “multimodal combinatorial therapy” which combines medicines and technology to attack fibrosis, perhaps all at once or possibly in stages.

Stephen Harrison says this information leaves him feeling like he is “very much at the very tip of the archeological dig” into what we know about treating Fatty Liver disease. He points out that one rule in drug development today is “if you get rid of the fat, the liver will take care of itself.” Following this logic, he suggests the best place for something like the mRNA/CAR-T approach might be in cirrhotic or pre-cirrhotic patients with the goal of regressing fibrosis sufficiently that other more metabolic drugs might become appropriate and adequate as therapy

Scott points out that 90% of all fatty livers never go on to develop cirrhosis. Given this fact, one key focus of learning must determine why it is that some livers progress and others do not. This would allow us to develop therapies targeted at the livers that progress and the cellular or genetic factors that lead them to do so. This, Scott points out, leads us back to the question of how we can use single-cell technologies to learn the role that each cell type plays at different points in disease progression. This leads to a discussion between Neil, Scott, and Stephen about the specific challenges of obtaining the liver tissue necessary for these kinds of assessments.

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