A Rapid Point of Care Test for APOL1 Renal Risk Alleles

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SUMMARY/ABSTRACT African Americans are disproportionately affected by chronic and end stage renal disease (ESRD); while 35% of patients on dialysis are African American, only 13.2% of the U.S. population is African American. One factor contributing to this disparity is genetic variation in apolipoprotein L1 (APOL1). APOL1 is a plasma protein of unknown cellular function that is protective against human sleeping sickness caused by most African trypanosomes but not Trypanosoma brucei rhodesiense or T.b gambiense. In humans, there are three main allelic variants of APOL1: G0 (wild-type), G1, and G2. The G1 and G2 APOL1 alleles (i.e. renal risk alleles) impart resistance to sleeping sickness, while the G0 allele enables parasite survival and infection. For this reason, the G1 and G2 alleles are prevalent in individuals with African ancestry. While beneficial for resisting sleeping sickness, the G1 and G2 variants are also associated with a greatly increased risk for ESRD and reduced allograft longevity in kidneys transplanted from donors with two risk alleles. Expression of just one copy of the G0 variant in kidney donors improves allograft longevity, reduces re-transplantations and eliminates the increased risk for ESRD associated with the G1/G2 risk variants, regardless of recipient APOL1 status. It follows that accurate risk assessment based on APOL1 variant expression in kidney donors is critical for kidney donor safety, donor informed consent, and the proper allocation of kidneys to recipients based on projected post- transplant survival. Additionally, substituting APOL1 status instead of African American race as a risk factor on the Kidney Donor Risk Index is predicted to remove unnecessary penalties applied to donors of African ancestry without two risk alleles, thus increasing the number of kidneys approved for transplant. However, current tests for APOL1 status are not FDA-cleared and require gene sequencing or mass-spectrometry which are technically challenging and infeasible during the 1-hour timeframe available for the pre-transplant risk evaluation of deceased donors (>70% of all kidney donors). Structural differences in the APOL1 variants, in combination with differential binding to a trypanosome protein, make this system a suitable target for assay development. Affinergy plans to develop a simple, rapid point of care test for the determination of APOL1 G0 status to inform healthcare decisions, improve risk stratification prior to transplantation of living and deceased donor kidneys, support informed donation decisions among living donors and potentially increase the number of available kidneys for donation. At the conclusion of Phase II, we expect to have a rapid test ready for verification and validation studies ahead of FDA clearance.