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

基本信息

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
项目类别：
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

项目摘要

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/摘要非裔美国人不成比例地受到慢性和终末期肾病 (ESRD) 的影响；而 35% 的接受透析的患者是非裔美国人，美国人口中只有 13.2% 是非裔美国人。一个因素造成这种差异的原因是载脂蛋白 L1 (APOL1) 的遗传变异。 APOL1 是一种血浆蛋白未知的细胞功能可以预防大多数非洲人引起的人类昏睡病锥虫，但不是罗得西亚布氏锥虫或冈比亚锥虫。人类主要有以下三种 APOL1 的等位基因变体：G0（野生型）、G1 和 G2。 G1 和 G2 APOL1 等位基因（即肾脏风险等位基因）赋予对昏睡病的抵抗力，而 G0 等位基因使寄生虫能够存活和感染。为了这因此，G1 和 G2 等位基因在非洲血统的个体中普遍存在。虽然有利于抵抗昏睡病、G1 和 G2 变异也与 ESRD 和 ESRD 风险大大增加有关具有两个风险等位基因的捐赠者移植的肾脏的同种异体移植寿命缩短。仅一份副本的表达肾脏捐献者中 G0 变异的移植可提高同种异体移植物的寿命，减少再移植并消除无论受体 APOL1 状态如何，与 G1/G2 风险变异相关的 ESRD 风险增加。如下：基于肾捐献者 APOL1 变异表达的准确风险评估对于肾捐献者至关重要安全性、捐赠者知情同意以及根据预计的术后情况将肾脏适当分配给受者移植存活率。此外，用 APOL1 身份代替非裔美国人种族作为风险因素肾脏捐赠者风险指数预计将消除对非洲血统捐赠者的不必要处罚没有两个风险等位基因，从而增加了批准移植的肾脏数量。然而，目前的测试 APOL1 状态未获得 FDA 批准，需要进行基因测序或质谱分析，这在技术上是困难的在可用于移植前风险评估的 1 小时时间内具有挑战性且不可行已故捐献者（> 70% 的肾脏捐献者）。 APOL1 变体的结构差异，结合与锥虫蛋白的差异结合，使该系统成为检测开发的合适目标。 Affinergy 计划开发一种简单、快速的护理点测试，用于确定 APOL1 G0 状态，以为医疗保健决策提供信息，在活体和死者移植之前改善风险分层捐献肾脏，支持活体捐献者知情的捐献决定，并有可能提高可供捐赠的肾脏数量。在第二阶段结束时，我们预计可以进行快速测试在 FDA 批准之前进行验证和确认研究。