Bioinformatics pipeline for personalized diagnostics of transplant rejection

Datirium, Llc, Cincinnati OH

Investigators

Abstract

Summary Transplantation is the most effective treatment for kidney failure, providing improved survival and quality of life. In the US, ~20,000-25,000 kidney transplants are performed in the US per year. Roughly ~90,000 individuals are waitlisted to receive a kidney allograft with average waiting time ~5 years. Many individuals die before receiving the transplant. Those patients receiving a transplant are required to be on life-long, maintenance immunosuppression (mIS) with calcineurin inhibitors (CNI), such as tacrolimus, to prevent rejection. Unfortunately, rejection still remains the #1 cause of death-censored graft loss. Potential treatment for graft failure is dialysis ($126K/year)1 or another transplant (~$500K) if another compatible kidney is available. Overall, in the US the annual cost of kidney transplant failure is $1.3B with ~ half covered by Medicare2. Thus, even a minor decrease in graft loss carries a potential for enormous human and economic benefit. Our preliminary and published data show that the scRNA/VDJ analysis of kidney biopsies and potentially urine samples can identify the alloreactive expanded cytotoxic T cell clones (CD8exp) that are likely causing rejection. We also showed that the analysis of gene expression in these clones can identify targets for anti- rejection therapy. The aim of the project is to develop a diagnostic test based on scRNA/VDJ analysis that will help physicians select personalized anti-rejection therapy based on the phenotype of the cells causing rejection. In this phase I project, we aim to (i) develop an automated computational pipelines that will process the data and produce a report for treating physician and (ii) to demonstrate the feasibility of completing the test within clinically reasonable time-frame. We will also collect preliminary data that will help justify a larger phase II study that will demonstrate the clinical benefit of the test.