Screening for Cardiac Amyloidosis with a Blood Biomarker in Minority Populations – SCABB-MP - Cardiac ATTR amyloidosis (ATTR-CA) is caused by the aggregation and deposition of the protein transthyretin in the heart, which leads to arrhythmias, congestive heart failure, and death. Although there are an estimated 25% of individuals over 80 years old that have these cardiac deposits, and there are 1.5 million at-risk Black individuals in the US who harbor a hereditary pathological transthyretin variant, ATTR-CA is often misdiagnosed, diagnosed too late, or never at all. This diagnostic problem is likely due to the variable ATTR-CA clinical presentation and the lack of simple, specific, and inexpensive diagnostic tests. This issue is exacerbated in Black and Hispanic communities, which are more likely to harbor a pathological gene variant but have been historically overlooked. The laboratory of PI Dr. Lorena Saelices Gomez has used the structures of cardiac fibrils extracted from ATTR-CA patients to design a peptide probe (Transthyretin Amyloid Detection 1, or TAD1) that robustly detects transthyretin aggregates in plasma of ATTR-CA patients. Our aim now is to validate TAD1 as a biomarker for ATTR-CA, bringing our technology a step closer to clinical application. In Aim 1, we will determine the ability of TAD1 to identify ATTR-CA in a cohort of Black and Hispanic individuals with heart failure. This cohort (n>600) has been extensively evaluated in the Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) study (R01HL139671, NCT03812172), the largest NIH funded ATTR-CA screening study for underrepresented minorities with heart failure, directed by co-PIs Drs. Mathew Maurer and Frederick Ruberg. We will capitalize on the biobanked samples and the comprehensive phenotypic and genotypic evaluation of this cohort to determine the diagnostic value of TAD1. We will assay plasma samples using our TAD1 assay and compare it to the current reference diagnostic test, PYP scintigraphy. In a subset of patients with elevated TAD1 signal, we will leverage a novel, highly-specialized imaging test for ATTR-CA using positron emission tomography (PET) imaging, to detect early ATTR-CA and investigate the interaction of ttr genotype with TAD1 levels. For Aim 2, our objective is to translate our TAD1 assay into a high throughput diagnostic ELISA tool, scalable for clinic use. We will first screen a polyclonal antibody panel generated in our laboratory and generate a fibril-specific monoclonal antibody from the best candidate. We will then optimize our peptide probes by yeast surface display. Finally, we will select the best probe and combine it to the monoclonal antibody to setup an ELISA assembly. We will validate this assembly with the samples used to develop the original TAD1 assay and the SCAN-MP cohort’s samples. The identification of ATTR-CA through a secure, affordable, and highly responsive test like this will facilitate early diagnosis. This, in turn, allows for the timely initiation of effective treatments during the initial stages of the disease when they are most beneficial.
