Detection and quantification of amyloidosis deposition and circulating amyloid fibrils in asymptomatic carriers of the V122I TTR allele

Virtually exclusive to individuals of African ancestry, the valine-to-isoleucine substitution at position 122 (V122I) variant in the transthyretin (TTR) protein is the most common cause of hereditary cardiac amyloidosis (ATTR- CA) worldwide. ATTR-CA causes progressive heart failure (HF) and has no proven benefit from standard HF treatments. Fortunately, new therapies that stabilize TTR improve morbidity and mortality in ATTR-CA, especially when prescribed early in the disease. However, early diagnosis is uncommon and conventional diagnostic tools lack diagnostic specificity to detect early disease. As such, a screening technique that directly assesses amyloid infiltration, without the need for cardiac biopsy, in V122I TTR carriers is a major unmet need. Thus, the objectives of this proposal are to determine the presence of amyloid in the blood by measuring circulating TTR amyloid aggregates (TAAs) and the presence of early cardiac amyloid infiltration with iodine-124 evuzamitide (I-124E) positron emission tomography (PET) imaging. The central hypothesis of this proposal is that V122I TTR carriers will have detectable blood and imaging evidence of ATTR-CA prior to disease onset. Two specific aims will test this hypothesis: Aim 1) determine the association of V122I TTR carrier status with circulating TAAs; Sub-aim 1.1) determine the association of TTR stabilizing therapy with circulating TAAs over time in patients with ATTR- CA; Sub-aim 1.2) Determine the association of circulating TTR amyloid aggregates with structural and functional evidence of amyloid infiltration and cardiac reserve; Aim 2) determine the association of V122I TTR carrier status with direct evidence of cardiac amyloid infiltration by I-124E; and Sub-aim 2.1) determine the association of circulating evidence of TTR amyloidosis with the amount of cardiac amyloid infiltration. All aims will leverage active investigation of a large cohort of V122I TTR carriers who have undergone deep clinical, imaging, and biomarker phenotyping (NCT05489549). In Aim 1, TAA levels will be measured and compared in a cohort of V122I TTR carriers without HF, non-carrier controls, and subjects with symptomatic ATTR-CA. Sub-aims 1.1 and 1.2 are substudies that will determine the longitudinal stability of TAA levels as well as their association with TTR-stabilizing treatment and evaluate the association of TAA levels with early pathophysiological evidence of cardiac amyloidosis by CMRI, respectively. In Aim 2, I-124E PET imaging will be used to measure and compare early cardiac amyloid infiltration in V122I TTR carriers, race-matched controls, and subjects with symptomatic ATTR-CA. Sub-aim 2 will evaluate the association of TAA levels with cardiac amyloid infiltration by I-124E PET. The research proposed is innovative, because it will, for the first time, employ two highly sensitive and specific techniques to detect and quantify amyloidosis in V122I TTR carriers: 1) detection of circulating TAAs by structure- based probes and 2) PET imaging with I-124E, a novel amyloid-binding peptide. Identifying amyloidosis prior to ATTR-CA disease onset will allow us to track the natural history of the disease and justify age-based screening strategies leading to reduced HF morbidity and mortality through earlier ATTR-CA recognition and treatment. Project Number: 1R01HL172993-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Justin Grodin | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $691,556 | Activity Code: R01 | Study Section: Cardiovascular and Respiratory Diseases Study Section[CRD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17299301A1