Non-racemic metabolic biomaterials for HFpEF

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Heart failure with preserved ejection fraction (НFpEF) is a syndrome that manifests in approximately 50% of all heart failure patients. The incidence and prevalence of НFpEF is sharply rising in the last years, however most patients remain unaddressed. One of the main reasons is the lack of efficacy of drugs, but the other is that historically HFpEF patients were excluded from many heart failure clinical trials. As a result, current treatment guidelines exist for other heart failure types, but completely lack for HFpEF. This proposal will develop a new class of biomaterial-based immunomodulators which work via targeted modulation of specific immune cells in HFpEF. These cells, namely monocytes and T-lymphocytes, are known to be responsible for HFpEF pathogenesis and their targeting is hypothesized to delay the onset of HFpEF and, possibly, alleviate its common consequence - cardiac fibrosis. We propose to develop such biomaterials and test them in mouse models of HFpEF through consecutive execution of the following Specific Aims: 1) We will synthesize and test these polymeric materials with the goal of developing lead formulations that will effectively tune activation of the immune cells in vitro; 2) We will test lead formulations in in vivo models of immune cell activation and further optimize our lead formulations; 3) We will thoroughly investigate best-performing materials in clinically-relevant mouse models of HFpEF. In addition, we will thoroughly investigate safety, including evaluation of systemic immunosuppression of these materials. Therefore, this proposal is significant, because targeting inflammatory and immune pathways proposed here could provide a promising approach for developing therapeutic options in HFpEF patients who have not yet responded adequately to approved and late-stage investigational treatments.