Developing novel fibrillin biomarkers for aortic disease

PROJECT SUMMARY In the United Statesaortic aneurysmal disease ranks among the topleading causes of deathPatients with aortic aneurysmsAAsare typically asymptomatic until dissection and then symptoms resemble other ailmentswhich can delay a correct diagnosisMortality associated with aortic dissectionADis high and rapid due to rupture of the aortaReducing mortality from aneurysmal disease requires increasing the early detection of AAs and improving the determination of when an AA is at risk for dissectionFibrillin fragments may be ideal blood based biomarkers for AAs and ADsFibrillinis the major protein component of elastic fiber microfibrilsand fragmentation of the aortic elastic lamellae is a hallmark pathological feature of AA and ADHigh concentrations of circulating fibrillinfragments have been shown to be associated with AAs and ADsFragments of fibrillinwhich is present in the core of the microfibril structureare less detectable than fibrillinfragments but detectable values show a similar extreme distributionQuantitation of fibrillin fragments is achieved using unique antibody pairs in sandwich ELISA assaysTwo antibody pairs for quantitating fibrillinfragments and one antibody pair for quantitating a fibrillinfragment have been selected to serve as biomarkersIn this Phase I applicationour aims are directed toward the future use of fibrillin fragments as biomarkers in an in vitro diagnosticIVDfor the detection and monitoring of AAsWe will conduct new clinical studies that are designed to establish the range of fibrillin fragment concentrations associated with small and large AAsStudies will also determine if the concentrations of fibrillin fragments are positively associated with increases in aneurysmal size in the same individualThese studiesalong with pre submission discussions with the FDAwill direct Phase II clinical studiesIn additionin preparing the ELISAs to be translated into commercial kitsthe reagents will be independently validated at the small business and the protocol optimized to make it suitable for clinical laboratory assaysThe manufacture of commercial ELISA kits and FDA guided clinical studies will occur in Phase II PROJECT NARRATIVE The long term goal of this project is the development of fibrillinand fibrillinbiomarkers for improved detection and monitoring of aortic aneurysms and dissectionsAneurysmal disease ranks among the topcauses of death because patients are often asymptomatic orwhen they present with symptomsare misdiagnosedInformative biomarkers will improve identification and management and reduce the mortality caused by this silent and lethal disease