Control of cardiac fibrosis to prevent cardiac function deterioration

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 DESCRIPTION: Cardiac fibrosis naturally occurs following myocardial infarction (MI). While the fibrotic tissue that forms initially protects the heart from rupture, continued cardiac fibrosis leds to a progressive decrease in cardiac function, and advances the infarcted heart towards heart failure. Accordingly, a therapy that can inhibit cardiac fibrosis from progressing at different stages of post-MI will preserve cardiac function and prevent the heart from evolving towards heart failure. However, there is currently no clinically approved therapy available. Myofibroblasts, formed primarily through TGFβ binding to the TGFβ receptor IIs (TGFβRIIs) on cardiac fibroblasts, are responsible for cardiac fibrosis. As such, to prevent cardiac fibrosis fro progressing, it is essential to inhibit the TGFβ pathway-mediated new myofibroblast formation, and to convert existing myofibroblasts back to cardiac fibroblasts. Yet current preclinical approaches, such as the systemic delivery of TGFβ inhibitors or anti-TGFβ antibodies, only decrease the content of active TGFβ in the heart, but do not inhibit the binding of TGFβ to TGFβRIIs, thus cannot fundamentally prevent myofibroblast formation. Besides, the systemic delivery causes dose-limiting side effects. While the use of TGFβRII inhibitors have the potential to prevent myofibroblast formation by blocking TGFβ from binding to TGFβRIIs, most of them are not suitable for cardiac anti-fibrotic therapy due to the effective dosages being always above the toxic level. The fundamental goal of this project is to create a peptide-based, low toxicity TGFβRII inhibitor, and its delivery system to efficiently inhibit TGFβ pathway-mediated cardiac fibrosis from progressing at different stages of post-MI, thus preventing cardiac function from progressive deterioration. In our preliminary studies, we have created a peptide based TGFβRII inhibitor ECG. It blocks the initial step of the TGFβ pathway ‒ TGFβ binding to TGFβRIIs. It specifically binds to the TGFβRIIs on cardiac fibroblasts without differentiating them into myofibroblasts. ECG also has a higher affinity for TGFβRIIs than TGFβ. Therefore, once the ECG binds to TGFβRIIs, TGFβ cannot bind to these receptors. ECG also pulls off those TGFβ already bonded to TGFβRIIs and occupies the receptors by itself. As a result, ECG is able to prevent TGFβ-induced myofibroblast differentiation, and revert myofibroblasts back to cardiac fibroblasts. To deliver ECG into infarcted hearts with high ECG retention in the tissue, and without causing dose-limiting side effects, we have developed an injectable and fast gelation hydrogel that can be specifically injected into infarcted hearts, can quickly solidify (<10 s) afte injection to efficiently retain ECG in the heart, and can gradually release ECG. Our preliminary in vivo study demonstrated that the hydrogel-based ECG release system attenuated cardiac fibrosis. Based on the above studies, we hypothesize that local delivery of hydrogel-based ECG release system into the infarcted heart will significantly attenuate cardiac fibrosis at different stages of post-MI, thus preventing cardiac function from progressive deterioration. The hypothesis will be tested through 2 specific aims: AIM #1 will test the hypothesis that optimal ECG release profiles will efficiently prevent cardiac fibroblasts from differentiating into myofibroblasts, and convert myofibroblasts back to cardiac fibroblasts. AIM #2 will test the hypothesis that ECG release systems will inhibit cardiac fibrosis from progressing in the infarcted hearts at different stages of post-MI to prevent progressive cardiac function deterioration.