Scientists in Italy have discovered three proteins that could prevent the death of cardiac muscle cells after a heart attack. By using a new in vivo screening method, they picked the three factors out of 1,198 proteins secreted by mouse cells into the animal’s bloodstream. When administered after a heart attack in mice, the proteins, Chrdl1, Fam3c and Fam3b, significantly reduced the damage to the cardiac muscle. This system for selecting promising therapeutics, described in a study in Science Translational Medicine, could be applied to other degenerative diseases1.
If blood flow to the heart is cut off, i.e. an infarction occurs, cardiac muscle cells start to die. Tissue necrosis continues to expand even after blood flow is restored. “When the damage is done, there isn’t much that we can do about it, as cardiomyocytes, the heart muscle cells, don’t have the ability to regenerate”, says Mauro Giacca, senior author of the paper, formerly director-general of the International Centre for Genetic Engineering and Biotechnology in Trieste, where the research started, and currently at King’s College, London and at the University of Trieste. A drug able to shield the cells from damage would change the game, he says.
The scientists created a library of 1198 genes, encoding for all the mouse proteins secreted outside the cells. They delivered these genes to cardiomyocytes by viral vectors, injecting them in vivo into mouse hearts. They pooled 50 genes per injection and injected one pool per mouse immediately after inducing infarction in the animals.
Each heart cell reached by a viral vector produced the corresponding proteins. The ones producing protective factors had higher probability to survive. Three weeks later, scientists examined cardiac tissue from the mice. “We used sequencing to look for transferred genes in survived heart cells, and compared their frequencies to the viral preparation before injection”, Giacca says. “Genes inducing protection were positively selected over the others, and we called this process FunSel, from functional selection.”
The method allowed the group to identify the three most effective proteins. Later, they investigated and described the protection mechanism too, and proved the three factors are equally effective when administered intravenously as proteins.
“We’ll test the three proteins in pigs and, in a couple of years, we hope to start clinical trials on human patients”, says Giacca, who has created a company to produce the factors. With a company he co-founded in 2020, Giacca is also using the FunSel platform to look for factors protecting kidney cells from the damage of chronic renal diseases.