A Rapid Point of Care Test for APOL1 Renal Risk Alleles

APOL1 肾脏风险等位基因的快速护理检测

• 批准号: 10441565
• 负责人: Martyn Darby
• 金额: $ 74.14万
• 依托单位: AFFINERGY, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441565
• 关键词: APOL1 gene; Address; Adoption; Affect; Affinity; African; African American; African American population; African Trypanosomiasis; African ancestry; Alleles; Allografting; Apolipoproteins; Binding; Biological Assay; Blood; Cell physiology; Chronic; Clinical; Decision Making; Detection; Development; Dialysis procedure; Disease Resistance; Donor person; Drops; End stage renal failure; Endogenous Factors; Engraftment; Enzyme-Linked Immunosorbent Assay; Evaluation; Genes; Genetic Variation; Genotype; Guidelines; Health; Health Personnel; Healthcare; Hour; Human; Immunoglobulin G; Individual; Infection; Informed Consent; Institutes; Instruction; Kidney; Kidney Diseases; Kidney Transplantation; Label; Laboratories; Lateral; Left; Libraries; Life; Living Donors; Longevity; Mass Spectrum Analysis; Methods; Mus; Parasites; Patients; Penetration; Performance; Phase; Plasma; Plasma Proteins; Population; Production; Protein Isoforms; Proteins; Race; Reagent; Recombinants; Reproducibility; Resistance; Risk; Risk Assessment; Risk Factors; Safety; Screening procedure; Serum; Specificity; System; Testing; Time; Transplantation; Trypanosoma; Trypanosoma brucei brucei; Variant; antibody detection; assay development; base; cohort; cost; cross reactivity; diagnostic accuracy; genetic variant; graft failure; high risk; improved; indexing; lateral flow assay; migration; novel; point of care testing; post-transplant; rapid test; risk stratification; risk variant; scale up; stability testing; success; validation studies; verification and validation

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.

摘要/摘要 非洲裔美国人受到慢性和末期肾脏疾病（ESRD）的影响不成比例。而35％ 透析患者是非裔美国人，只有13.2％的美国人口是非裔美国人。一个因素 导致这种差异的是载脂蛋白L1（APOL1）的遗传变异。 apol1是一种血浆蛋白 未知的细胞功能，可防止大多数非洲人引起的人类眠病 锥虫，而不是锥虫brucei Rhodesiense或T.B gambiense。在人类中，有三个主要 Apol1：G0（野生型），G1和G2的等位基因变体。 G1和G2 APOL1等位基因（即肾脏风险等位基因） 赋予对睡眠疾病的抵抗力，而G0等位基因可实现寄生虫的生存和感染。为了这 原因，G1和G2等位基因在非洲血统的个体中很普遍。虽然有益于抵抗 睡眠疾病，G1和G2变体也与ESRD和ESRD风险大大相关 从具有两个风险等位基因的供体移植的肾脏中的同种异体移植寿命降低。只有一个副本的表达 肾脏供体的G0变体中有同种异体移植的寿命，减少了重新转移并消除了 与G1/G2风险变体相关的ESRD风险增加，而与接受者APOL1状态无关。跟随 基于肾脏供体中APOL1变体表达的准确风险评估对于肾脏供体至关重要 安全性，捐助者知情同意，以及根据预计的后 移植生存。此外，将APOL1身份代替而不是非裔美国人种族作为风险因素 预计肾脏捐赠者风险指数将消除对非洲血统捐助者的不必要处罚 没有两个风险等位基因，因此增加了批准移植的肾脏数量。但是，当前测试 对于apol1状态未清除FDA，需要基因测序或质谱法，这在技术上是 在1小时的时间范围内具有挑战性和不可行，可用于移植前风险评估 已故捐助者（> 70％的肾脏捐助者）。 APOL1变体的结构差异，结合 与锥虫蛋白的差异结合，使该系统成为测定开发的合适靶标。 Affinergy计划为确定APOL1 G0状态的简单，快速的护理测试 向医疗保健决策提供信息，在移植生命之前改善风险分层 捐助者肾脏，支持知情的捐助者的捐赠决定，并有可能增加 可用捐赠的肾脏数量。在第二阶段结束时，我们希望准备快速测试 用于验证和验证研究之前。