A novel clinical assay for detection of APOL1 renal risk alleles

SUMMARY ABSTRACT African Americans are disproportionately affected by chronic and end stage kidney diseasewhileof patients on dialysis are African Americanonlyof the U Spopulation is African AmericanOne factor contributing to this disparity are genetic variations in apolipoprotein LAPOLAPOLis a plasma protein protective against human sleeping sickness caused by the parasite Trypanosoma brucei rhodesienseIn humansthere are three allelic variants of APOLGwildtypeGand GThe Gand GAPOLallelesi erenal risk allelesimpart resistance to sleeping sicknesswhile the Gallele promotes parasite survival and infectionFor this reasonthe Gand Galleles are found almost exclusively in African and African American populationsWhile beneficial for resisting sleeping sicknessthe Gand Gvariants are also associated with a greatly increased risk for end stage renal diseaseMoreoverin the renal transplantation settingthe presence of any two risk allelesGGGGor GGin the donor kidney is strongly associated with poor graft survivalwhereas the presence of just one copy of the Gallele completely eliminates this increased riskGGGGGGAs a resultAfrican Americans are at a higher risk for end stage renal disease and donor kidneys containing two APOLrenal risk alleles may not be suitable for transplantationIt is therefore essential that donors are screened for APOLrenal risk alleles prior to kidney donationUnfortunatelythe current gold standard for genotyping APOLrequires gene sequencing and is technically infeasible during the limited time frame for triaging deceased donor organsStructural differences in the APOLvariantsin combination with differential binding to a parasite proteinmake this system a suitable target for assay developmentAffinergy plans to develop a simplerapidand affordable peptide based detection system for the qualitative assessment of APOLGstatus to improve risk stratification during renal transplantationAt the conclusion of Phasewe expect to have a technology that can be developed into a diagnostic assay in Phasefor use by clinicians and researchers to quickly assess for kidney disease risk through the rapid detection of APOLGin plasma PROJECT NARRATIVE APOLa protein protective against African sleeping sicknesshas three variantsGGand Gthe Gand Gvariantsfound predominantly in African and African American populationsconvey disease resistance but also greatly increase the risk for kidney disease while just one copy of the wildtype APOLGvariant eliminates this riskIn kidney transplantationdonor kidneys containing two APOLrenal risk alleles fare poorly following transplant but the only way to determine APOLstatus is through gene sequencingwhich is expensive and has a slow turnaround time incompatible with pre transplant assessmentIn this Phase I applicationwe propose to develop a novel diagnostic assay that can rapidly demonstrate the presence or absence of the wildtype APOLGprotein for use in kidney transplant risk stratification