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FIRST LOOK: Novel Target Discovery Pipeline for Calcific Aortic Valve Disease

Aortic stenosis due to calcific aortic valve disease (CAVD) is the most prevalent valvular disorder and is on the rise as the population ages. Left untreated CAVD has a dismal prognosis, inevitably leading to death. Annually, in the US alone, 80,000 patients progress to severe CAVD, requiring aortic valve intervention and at a cost of over $20 billion. Despite these clinical and economic burdens, no medical therapies are available for CAVD. The only existing treatment options are the invasive and costly surgery or transcatheter valve replacement. Further research is thus necessary to identify key molecular mechanisms and develop new drug targets for CAVD.

Calcifying extracellular vesicles (100-300 nm), released from cardiovascular cells, aggregate and nucleate microcalcifications (Nature Materials 2016; JCI 2016). This process lies below the resolution of standard clinical imaging modalities, a major barrier to overcome in this field. Our recent studies demonstrated that high-resolution microscopy and molecular imaging combined with nanoparticle tracking analysis, and a novel 3D-bioprinting technology modeling the native valve leaflet, can visualize and quantify vesicle-derived microcalcifications, providing a powerful tool for exploring this process in vivo and in vitro (Figure 1).

My current research aims at discovering novel therapeutic targets for CAVD. The cross-disciplinary collaboration among innovative clinical and basic science investigators at BWH has utilized cutting-edge techniques to establish the CAVD Discovery Pipeline (Figure 2). This project expedites the translation of basic research findings into clinic by integrating clinical parameters and PET/CT imaging obtained from patients before valve surgery, with post-operative pathology, proteomics, transcriptomics, single cell analysis, and multi-dimensional network analysis, thereby creating an integrated map of human CAVD.

Our results will provide insight into mechanisms that identify early stages of disease that will ultimately permit early therapy in patients with subclinical valve disorders and help select personalized treatment options. Moreover, our results will lead to patentable products (e.g., diagnostic databases, therapeutics, imaging and laboratory probes) that will immediately impact CAVD research, diagnosis and therapy.

For more information about Dr. Aikawa’s research, please contact Partners HealthCare Innovation by clicking here.