Gene Therapy for Regeneration Works. Are Humans Next?
Channel: Lifespan News
Date: 2023-02-18

Some animals, like zebrafish, can regenerate their body, their brain, retina, spinal cords, heart, and other complex tissues. And soon we might be able to as well.

The journal Cell Stem Cell has published a study about animals that have been given the zebrafish-like ability to restore their heart muscle after injury. According to the paper you don’t want genes responsible for regeneration stuck in the on position. That’s how you get tumors. In zebrafish, these genes are controlled by TREEs (Tissue Regeneration Enhancer Elements). TREEs only turn on regenerative genes when they sense an injury. 

Heart tissue does not normally regenerate in adult mammals, but in two similar experiments researchers genetically engineered mice to express TREEs in a way that would show visual indicators only during injury response. In uninjured mice, there was no gene expression, but in the injured mice, the TREE indicator was clearly visible. The best part? It worked whether the injection was given before or immediately after the injury.

Similar results were seen in pigs. They didn’t have enough virus to infect the entire pig so they just injected the pig's hearts. The point is even with just treating the heart they got similar results to the mice. The indicators were only visible at the injury sites.

The final experiments involved a molecule called Yap. Yap is a transcriptional cofactor that causes rapid cell growth and division when overexpressed. Without a TREE, genetically modifying animals to express Yap in the heart kills them within days due to cardiac muscle overgrowth.

But with this new TREE method things were much different in the final test: restoring heart function. Using TREEs to control Yap expression, they were able to restore core metrics of cardiac function. This occurred whether the injection was given before or immediately after the injury, and it provided improvements in function over an injured control group. Yap was only expressed during injuries and only at injury sites, basically it turned off after the injury was healed.

This is a proof-of-principle study showing that tissue regeneration and gene therapy is a plausible and effective approach in animal models. While this is not yet a human clinical trial, it is a significant step towards one and has the potential to become the standard of care for treating heart attacks or other conditions that cause significant tissue damage.

SOURCES AND FURTHER READING
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Gene Therapy for Heart Regeneration in Living Animals - https://www.lifespan.io/news/gene-therapy-for-heart-regeneration-in-living-animals/

An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair - https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00459-3

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