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RNA Injections Shown to Rebuild Damaged Heart Muscle

Cardiomyocytes in a mouse heart

Cardiomyocytes, in green, grown in a mouse heart after gel injection (University of Pennsylvania)

30 November 2017. Engineers and medical researchers developed a technique to deliver genetic material into damaged heart muscle that in lab mice regrows heart cells. A team from the engineering and medical schools at University of Pennsylvania in Philadelphia published its findings in the 27 November issue of the journal Nature Biomedical Engineering (paid subscription required).

Researchers led by cardiovascular researcher Edward Morrisey and biomedical engineering professor Jason Burdick are seeking better treatments for damage to heart muscle caused by heart attacks. A heart attack occurs when oxygen and nutrients supplied to heart muscles in coronary arteries are reduced or cut off, such as from blood clots that form around the build-up of plaques in the arteries. When starved for oxygen and nutrients, heart muscles become damaged or die, causing a life-threatening condition. American Heart Association says a heart attack occurs about every 40 seconds in the U.S.

Heart muscles are not able to regenerate, which limits recovery from heart attacks and increases the mortality of people who suffer a heart attack. Possible solutions include regenerating heart tissue in the lab from stem cells into healthy heart muscle cells called cardiomyocytes, or fixing the damaged heart tissue with a surgically implanted patch containing cardiomyocytes. Morrisey, Burdick, and colleagues instead sought a more direct treatment that regenerates heart muscle cells from inside the heart.

The UPenn team looked into ways of delivering micro RNA into the damaged heart muscles to restart cell production. Micro RNAs or miRNAs, are genetic molecules that serve as regulators of the genome. They start out small, but evolve into more complex molecules that interact with another type of RNA — messenger RNA — to control the expression of genes responding to various proteins.

The researchers identified a specific type of miRNA, known as miR-302 that regulates cardiomyocyte growth and development in prenatal and infant heart muscle. But miRNAs are unstable and break down quickly, which requires a method for delivering a high-enough dose into damaged heart muscles to be effective. Micro RNAs in high doses also pose a risk of instigating tumors, since they promote cell proliferation.

In lab cultures, the miR-302 concentrations encouraged cardiomyocyte regeneration for a week, but a method was still needed to deliver the miRNAs into damaged heart muscles. For this task, the team used a hydrogel, a water-based polymer with hyaluronic acid, a natural substance fund in the eyes and other fluids in the body. As reported in Science & Enterprise, Burdick’s lab showed in 2014 hydrogels could deliver enzymes directly into the heart as a possible preventive treatment for heart attacks.

“The most important traits of this gel are that it’s shear-thinning and self-healing,” says Burdick in a university statement. “Shear-thinning means it has bonds that can be broken under mechanical stress, making it more fluid and allowing it to flow through a syringe or catheter.  Self-healing means that when that stress is removed, the gel’s bonds re-form, allowing it to stay in place within the heart muscle.”

Tests in lab mice induced with heart damage showed that a single injection of the hydrogel with miRNAs results in cardiomyocyte proliferation for 2 weeks. Mice receiving the injections also show better heart performance on a number of indicators, including ejection fraction, the percentage of blood that’s pumped out of a filled ventricle with each heart beat.

The authors conclude that the delivery of miRNAs with a biocompatible hydrogel is a promising treatment candidate for regenerating heart tissue, and the team plans to test the process further, including in pigs with hearts similar to humans. The university also filed provisional patents for the technology.

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Updated 30 November 2017, to fix usage error in third paragraph.

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