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This very interesting work involves identifying enhancer DNA sequences that regulate regeneration in an exceptionally regenerative species, such as zebrafish, and introducing these sequences into mammals via gene therapy. The researchers find a sequence that can be used to regulate expression of genes that drive heart regeneration following injury, a desirable goal given that mammalian hearts regenerate poorly. Zebrafish are capable of scarless healing of heart injuries, and connecting the zebrafish enhancer to mammalian growth genes can improve regeneration, by expressing these genes at the appropriate time in the context of repair of injury.

Researchers borrowed a segment of zebrafish DNA that they call a TREE, tissue regeneration enhancer element. TREEs are a family of gene enhancers included in the genome that are responsible for sensing an injury and orchestrating the activity of repair-related genes for reconstruction in a specific place. These enhancers also can shut off gene activity as healing is completed. These regulatory elements have been found in fruit flies, worms, and mice as well as the zebrafish. "We probably have them too, but it's just easier for us to find them in zebrafish and ask if they work in mammals."

About 1,000 nucleotides long, these enhancer sequences are bristling with recognition sites for different factors and stimuli to attach and change gene activity. "We don't fully understand how they do this and what they're truly responding to. Different cell types within an animal also have different types of these enhancers. Some of them are responsive in multiple tissues - those are the ones we use here. But when we profile regenerating spinal cord or fins in fish, we get different sequences. There may be tens of thousands of these types of enhancers in the human genome."

Rsearchers wanted to know if they could selectively incorporate the enhancer elements into an adult mouse using adeno-associated virus, a familiar gene therapy tool for introducing gene sequences into cells. The virus introduced DNA containing an enhancer to all tissues, but the hope was that the TREEs would only become active in response to an injury. A series of experiments in heart attack models of mice showed that viruses containing a TREE could be infused a week before injury and then the enhancer would jump into action when it detected injury. But they found it also worked when introduced to the animal a day or two after the heart attack.

Then, to see if this system could actually repair damage, rather than just sensing damage and turning on a gene that lights up tissue, they delivered a hyperactivated form of YAP, a powerful tissue growth gene that is implicated in cancer. The key question was whether this "really potent hammer" that can make cell division run amok could be lassoed into working only in the right time and place. They used a mutated YAP controlled by a TREE to see whether they could have safe growth of muscle after a heart attack in mice. The TREE turned on a mutated YAP for a few weeks, just in the injury site, and then it naturally shut down expression. The treatment caused muscle cells to begin to divide and the mouse's heart returned to near normal function after several weeks, though not without some scarring.

Link: https://today.duke.edu/2022/12/gene-therapy-heart-attacks-mice-just-got-more-precise