Although the heart tries to rebuild itself after a heart attack, the process is difficult because of inflammation and scarring. Because the heart is unable to regenerate, its function declines, and the unrepaired damage can lead to future heart episodes, as Arlene Weintraub explained in Fierce Biotech.
Scientists at Vanderbilt University may have an answer to improving cardiac recovery. It comes from a compound in Roche’s library that was originally intended to treat rheumatoid arthritis. The scientists demonstrated with mouse models that the drug, SYN0012, could change the way in which the heart responds to inflammation after a heart attack, leading to an improvement in cardiac functioning and reported the results in the journal JCI Insight.
According to the journal article, the scientists induced MI “by ligation of the left anterior descending artery in mice with either heterozygous or homozygous knockout of CDH11, wild-type mice receiving bone marrow transplants from Cdh11-deficient animals, and wild-type mice treated with a functional blocking antibody against CDH11 (SYN0012).” Using flow cytometry, they found that there was “significant CDH11 expression in noncardiomyocyte cells after MI.”
Animals who were given SYN0012 had improved cardiac function, “as measured by echocardiogram, reduced tissue remodeling, and altered transcription of inflammatory and proangiogenic genes.” They added, “Targeting CDH11 reduced bone marrow–derived myeloid cells and increased proangiogenic cells in the heart 3 days after MI. Cardiac fibroblast and macrophage interactions increased IL-6 secretion in vitro.”
The scientists concluded that CDH11-expressing cells appear to “contribute to inflammation-driven fibrotic remodeling after MI and that targeting CDH11 with a blocking antibody improves outcomes by altering recruitment of bone marrow–derived cells, limiting the macrophage-induced expression of IL-6 by fibroblasts and promoting vascularization.” The repurposed compound seems to help the heart to repair itself.
The researches explained that SYN0012 works by blocking the protein cadherin-11, a major cause of inflammation of heart tissue. In the mice, SYN0012 increased the recruitment of cells to the heart that appeared to help rebuild blood vessels. It limited the activity of fibroblasts, cells that help remodel the heart after a heart attack, so the process would not create too much scarring.
According to senior author W. David Merryman, Ph.D., professor of biomedical engineering, pharmacology, medicine and pediatrics at Vanderbilt, “Some amount of inflammation is necessary in myocardial infarction. Inhibiting cadherin-11 could allow more precise control over the amount of inflammation in the fibrotic remodeling process.”
Roche Innovation Center in Basel was the supplier of the SYN0012 used in the Vanderbilt study. Roche wanted to target cadherin-11 in rheumatoid arthritis, but it sidelined that research effort in 2018 as part of an effort to focus on other aspects of its pipeline.
The objective of the Vanderbilt research is to fine tune the inflammation after a heart attack, rather than stopping it completely. As Merryman concluded, “Importantly, targeting [cadherin-11] with SYN0012 in mice does not prevent the acute inflammatory and reparative response, but rather it selectively acts on several cell populations to reduce the duration of inflammation and the extent of fibrotic remodeling.