In the United States, aortic aneurysmal disease ranks among the top 20 leading causes of death. Patients with aortic aneurysms (AAs) are typically asymptomatic until dissection and then symptoms resemble other ailments, which can delay a correct diagnosis. Mortality associated with aortic dissection (AD) is high and rapid due to rupture of the aorta. Reducing mortality from aneurysmal disease requires increasing the early detection of AAs and improving the determination of when an AA is at risk for dissection. Fibrillin fragments may be ideal blood-based biomarkers for AAs and ADs. Fibrillin-1 is the major protein component of elastic fiber microfibrils, and fragmentation of the aortic elastic lamellae is a hallmark pathological feature of AA and AD. High concentrations of circulating fibrillin-1 fragments have been shown to be associated with AAs and ADs. Fragments of fibrillin-2, which is present in the core of the microfibril structure, are less detectable than fibrillin- 1 fragments but detectable values show a similar extreme distribution. Quantitation of fibrillin fragments is achieved using unique antibody pairs in sandwich ELISA assays. Two antibody pairs for quantitating fibrillin-1 fragments and one antibody pair for quantitating a fibrillin-2 fragment have been selected to serve as biomarkers. In this Phase I application, our aims are directed toward the future use of fibrillin fragments as biomarkers in an in vitro diagnostic (IVD) for the detection and monitoring of AAs. We will conduct new clinical studies that are designed to establish the range of fibrillin fragment concentrations associated with small and large AAs. Studies will also determine if the concentrations of fibrillin fragments are positively associated with increases in aneurysmal size in the same individual. These studies, along with pre-submission discussions with the FDA, will direct Phase II clinical studies. In addition, in preparing the ELISAs to be translated into commercial kits, the reagents will be independently validated at the small business and the protocol optimized to make it suitable for clinical laboratory assays. The manufacture of commercial ELISA kits and FDA-guided clinical studies will occur in Phase II.
The long-term goal of this project is the development of fibrillin-1 and fibrillin-2 biomarkers for improved detection and monitoring of aortic aneurysms and dissections. Aneurysmal disease ranks among the top 20 causes of death because patients are often asymptomatic or, when they present with symptoms, are misdiagnosed. Informative biomarkers will improve identification and management and reduce the mortality caused by this silent and lethal disease.
