SBIR-STTR Award

Direct to Phase II

African Americans are disproportionately affected by chronic and end stage renal disease (ESRD); while 35% ofpatients on dialysis are African American, only 13.2% of the U.S. population is African American. One factorcontributing to this disparity is genetic variation in apolipoprotein L1 (APOL1). APOL1 is a plasma protein ofunknown cellular function that is protective against human sleeping sickness caused by most Africantrypanosomes but not Trypanosoma brucei rhodesiense or T.b gambiense. In humans, there are three mainallelic 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 thisreason, the G1 and G2 alleles are prevalent in individuals with African ancestry. While beneficial for resistingsleeping sickness, the G1 and G2 variants are also associated with a greatly increased risk for ESRD andreduced allograft longevity in kidneys transplanted from donors with two risk alleles. Expression of just one copyof the G0 variant in kidney donors improves allograft longevity, reduces re-transplantations and eliminates theincreased risk for ESRD associated with the G1/G2 risk variants, regardless of recipient APOL1 status. It followsthat accurate risk assessment based on APOL1 variant expression in kidney donors is critical for kidney donorsafety, 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 onthe Kidney Donor Risk Index is predicted to remove unnecessary penalties applied to donors of African ancestrywithout two risk alleles, thus increasing the number of kidneys approved for transplant. However, current testsfor APOL1 status are not FDA-cleared and require gene sequencing or mass-spectrometry which are technicallychallenging and infeasible during the 1-hour timeframe available for the pre-transplant risk evaluation ofdeceased donors (>70% of all kidney donors). Structural differences in the APOL1 variants, in combination withdifferential 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 toinform healthcare decisions, improve risk stratification prior to transplantation of living and deceaseddonor kidneys, support informed donation decisions among living donors and potentially increase thenumber of available kidneys for donation. At the conclusion of Phase II, we expect to have a rapid test readyfor verification and validation studies ahead of FDA clearance.

Public Health Relevance Statement:
PROJECT NARRATIVE APOL1, a trypanolytic protein that in some forms (called G1 and G2) is protective against African sleeping sickness and is found predominantly in individuals of African ancestry. ApoL1 G1 and G2 convey disease resistance but also greatly increase the risk for kidney disease, while even one copy of the gene for wild-type APOL1 G0 variant eliminates this risk. In this Direct to Phase II application, we propose to develop a novel rapid test to show the presence of G0 in blood that can be available to all healthcare providers to inform healthcare decisions and improve kidney transplantation success.

Project Terms:
Adoption ; Affect ; Alleles ; Allelomorphs ; Apolipoproteins ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood ; Blood Reticuloendothelial System ; Cell physiology ; Cell Function ; Cell Process ; Cellular Function ; Cellular Physiology ; Cellular Process ; Subcellular Process ; Decision Making ; Dialysis procedure ; Dialysis ; dialysis therapy ; Donor person ; transplant donor ; Enzyme-Linked Immunosorbent Assay ; ELISA ; Genes ; Genotype ; Health ; Health Personnel ; Health Care Providers ; Healthcare Providers ; Healthcare worker ; health care personnel ; health care worker ; health provider ; health workforce ; healthcare personnel ; medical personnel ; treatment provider ; Human ; Modern Man ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; indexing ; Infection ; Informed Consent ; Institutes ; Kidney ; Kidney Urinary System ; renal ; Kidney Diseases ; Nephropathy ; Renal Disease ; kidney disorder ; renal disorder ; Kidney Transplantation ; Kidney Grafting ; Kidney Transplants ; Renal Grafting ; Renal Transplantation ; Renal Transplants ; kidney tx ; Laboratories ; Libraries ; Longevity ; Length of Life ; life span ; lifespan ; Methods ; Mus ; Mice ; Mice Mammals ; Murine ; Parasites ; Patients ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Plasma Proteins ; Production ; Proteins ; Race ; Racial Group ; Racial Stocks ; Reagent ; Risk ; Risk Factors ; Safety ; Specificity ; Mass Spectrum Analysis ; Mass Photometry/Spectrum Analysis ; Mass Spectrometry ; Mass Spectroscopy ; Mass Spectrum ; Mass Spectrum Analyses ; Testing ; Time ; Transplantation ; transplant ; Trypanosoma ; Trypanosome ; Trypanosoma brucei brucei ; T brucei ; T. brucei ; Trypanosoma brucei ; African Trypanosomiasis ; African Sleeping Sickness ; sleeping sickness ; Genetic Variation ; Genetic Diversity ; African American ; Afro American ; Afroamerican ; Black Populations ; black American ; Healthcare ; health care ; Risk Assessment ; Guidelines ; base ; Label ; improved ; Left ; Lateral ; Chronic ; Clinical ; Penetration ; Phase ; Variant ; Variation ; Evaluation ; Screening procedure ; screening tools ; Serum ; Blood Serum ; Individual ; African ; Engraftment ; Living Donors ; Life ; Hour ; System ; Allografting ; Performance ; Isoforms ; Protein Isoforms ; success ; Accuracy of Diagnosis ; diagnostic accuracy ; cohort ; Structure ; novel ; validation studies ; assay development ; cross reactivity ; Drops ; resistance to disease ; resistant disease ; resistant to disease ; Disease Resistance ; Molecular Interaction ; Binding ; ESRD ; End-Stage Kidney Disease ; End-Stage Renal Disease ; End stage renal failure ; Address ; Affinity ; Detection ; Recombinants ; Reproducibility ; Endogenous Factors ; Development ; developmental ; Instruction ; cost ; genetic variant ; Gene variant ; allele variant ; allelic variant ; genomic variant ; scale up ; Population ; migration ; Resistance ; resistant ; graft failure ; high risk ; stability testing ; verification and validation ; risk variant ; Risk-associated variant ; risk allele ; risk gene ; risk genotype ; risk loci ; risk locus ; APOL1 gene ; APOL-I ; APOL1 ; risk stratification ; stratify risk ; post-transplant ; post-transplantation ; posttransplant ; posttransplantation ; lateral flow assay ; lateral flow test ; antibody detection ; antibody based detection ; detect antibodies ; rapid test ; rapid assay ; rapid tests ; point of care testing ;