Peptides derived from soluble extracellular matrix for promoting improved healing following myocardial infarction

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Summary: Cardiovascular disease is the leading cause of death in the United States and there are limited treatments options available for preventing the functional decline to heart failure following a significant myocardial infarction (MI). One more recent promising approach is the use of acellular biomaterials to alter the remodeling response by mechanical means, biochemical means, or both. One specific biological material that has shown great promise in pre-clinical studies is adult porcine ventricular cardiac extracellular matrix (ECM) which recently successfully completed Phase I clinical trials. However, sourcing of the porcine hearts to generate the material can be difficult and maintaining consistency in a product as complex as cardiac ECM is challenging. Further, we, and others, have demonstrated that ECM derived from earlier developmental time points is more regenerative than ECM derived from adult tissues, but supply issues are even greater for younger hearts at the scale necessary to generate a therapeutic. Recent work form our group suggests that the specific beneficial effects of solubilized ECM may be traced to a smaller set of specific ECM proteins or peptides present in the soluble matrix. Identification and characterization of the set of specific peptides in soluble ECM that promote better healing post- myocardial infarction could lead to a more consistent and reliable therapeutic option for treating remodeling post- MI. Our hypotheses, based on significant preliminary data from our own group and others, are 1) that specific peptides present in early developmental age cardiac ECM will promote a more regenerative healing response in adult injury than solubilized adult ventricular ECM and 2) that by identifying these peptides and developing delivery methods that promote their persistence while aiding in neo-tissue formation, we will more effectively repair the heart following MI. To test this hypotheses, we will carry out three aims. In the first aim we will assess whether ECM derived from fetal porcine hearts promotes improved healing and functional repair to a greater extent than adult porcine cardiac extracellular matrix. We will induce MI through ischemia-reperfusion injury and compare cardiac remodeling and function between injections of adult or fetal cardiac ECM. In the second aim, we will isolate and characterize specific peptides derived from cardiac ECM that promote regenerative phenotypes in cells relevant to cardiac healing and repair. We will carry out a novel blot culture method previously developed by our lab to identify and characterize peptides in solubilized ECM that promote specific cell responses, synthesize them and assess the mechanism of action for identified fragments. In the third aim we will develop a biomaterial delivery system for delivering soluble cardiac ECM or peptide derivatives of cardiac ECM to enhance persistence of the regenerative effects and promote neo-tissue formation, utilizing silk as the carrier material. If successful we envision a new class of peptide therapeutics for treating the injured heart that is more standardized, easier to manufacture and potentially more beneficial, as well as a new deliver strategy that enhances the persistence of the ECM/ peptides and promotes better healing following MI.