Personalized Dilated Cardiomyopathy

Background

Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a serious medical condition that affects approximately 1 in every 250 people.

In DCM, the heart muscle dilates but cannot contract normally, making it difficult to efficiently pump blood. It is one of the main causes of heart failure and the leading reason for heart transplantations. The disease can stay dormant for years until it aggressively breaks out and is usually terminal. Currently, diagnosis and management of DCM relies entirely on in-hospital medical procedures including echocardiography, heart biopsies and genetic testing.

Drs. Davis, Demirci, Ashley, Parikh and Steinmetz are collaborating to establish new tools to diagnose and monitor diseases. They are testing the ability of different technologies to reliably detect molecular biomarkers in complex human specimens, including in blood, urine and saliva. Their goal is to produce rapid, reliable and cost-effective devices that will not only improve patient care, but are suitable for use by healthcare providers at the point of care.

Project

Identification of diagnostic and prognostic markers for RBM20-deficient Dilated Cardiomyopathy

There is clear evidence that a gene called RBM20 plays a key role in familial DCM. RBM20 encodes a protein that helps process (or “splice”) RNA molecules in the heart. Mutations in this gene are responsible for approximately 3-5% of all cases of DCM.

Building on their joint expertise in genomics, technology development, and engineering, Drs. Davis, Ashley and Steinmetz aim to develop cheap, cost-effective, and label-free nanoelectronic devices that detect putative DCM biomarkers from patient samples in real-time. As Director of the Stanford Center for Inherited Cardiovascular disease, Dr. Ashley provides a direct connection to patient’s suffering from DCM. Using patient samples provided by Dr. Ashley’s lab, members of the Steinmetz lab are using different full-length RNA sequencing techniques to identify promising DCM biomarkers. Meanwhile, members of the Stanford Genome Technology Center (directed by Dr. Davis and Steinmetz) are using a biosensor platform developed to quantify sequence-specific nucleic acid hybridization and detect specific biomarkers from patient samples.

By combining their complementary strengths and expertise, these three labs hope to quickly progress their project towards clinical applications. In addition, they expect the resulting platform technology to be applicable to many other diseases that are similarly unaddressed in the current clinical landscape.

Publications:

_{^{1. Briganti F*, Sun H*, Wei W, Wu J, Zhu C, Liss M, Karakikes I, Rego S, Cipriano A, Snyder M, Meder B, Xu Z, Millat G, Gotthardt M, Mercola M & Steinmetz LM#. iPSC modelling of RBM20-deficient DCM identifies upregulation of RBM20 as a therapeutic strategy. Cell Reports, (2020)

2. Schneider JW, Oommen S, Muhammad YQ, Goetsch SC, Pease DR, Sundsbak RS, Guo W, Sun M, Sun H, Kuroyanagi H, Webster DA, Coutts AW, Holst KA, Edwards BS, Newville N, Hathcock MA, Melkamu T, Briganti F, Wei W, Romanelli MG, Fahrenkrug SC, Frantz DE, Olson TM, Steinmetz LM, Carlson DF, Nelson TJ. A ribonucleoprotein-granulepathway to heart failure in human RBM20 cardiomyopathy gene-edited pigs. Nature Medicine (2020).

3. Parikh VN, Caleshu C, Reuter C, Lazzeroni LC, Ingles J, Garcia J, McCaleb K, Adesiyun T, Sedaghat-Hamedani F, Kumar S, Graw S, Gigli M, Stolfo D, Dal Ferro M, Ing AY, Nussbaum R, Funke B, Wheeler MT, Hershberger RE, Cook S, Steinmetz LM, Lakdawala NK, Taylor MRG, Mestroni L, Merlo M, Sinagra G, Semsarian C, Meder B, Judge DP, Ashley EA. Regional variation in RBM20 causes a highly penetrant arrhythmogenic cardiomyopathy. Circ Heart Fail. (2019).}^{4. Rego S, Dagan-Rosenfeld O, Zhou W, Sailani MR, Limcaoco P, Colbert E, Avina M, Wheeler J, Craig C, Salins D, Röst HL, Dunn J, McLaughlin T, Steinmetz LM, Bernstein JA, Snyder MP. High-frequency actionable pathogenic exome variants in an average-risk cohort. Cold Spring Harb Mol Case Stud. (2018).}}