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Report for Clinical Trial NCT02082821

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Pure-Heart-1: A P2X7R Single Nucleotide Mutation Promotes Chronic Allograft Vasculopathy

Heart transplantation (HT) is a lifesaving procedure for patients with end-stage heart failure and provides a better survival and quality of life if compared to medical treatment. HT is subject to alloimmune response, which, if left uncontrolled, is capable of jeopardizing long-term cardiac function. Advances in immunosuppression have enhanced the survival of HT patients. Nearly 2500 HT per year have been performed in the US during the last 10 years and despite significant improvements, long-term survival rates remain poor. More than 20% of patients do not survive more than 3 years, and those who survive are afflicted by long-term complications of alloimmunity and chronic immunosuppression. Life expectancy of patients who lose cardiac allografts is dramatically poor due to the absence of any therapeutic tool apart from re-transplantation, which is plagued by poor outcomes. The identification of novel therapeutic targets is thus mandatory. ATP/P2X7R signaling in T cells is highly relevant for cardiac allograft survival. ATP is a small molecule present at high concentrations inside cells; it is released as extracellular ATP (eATP) following cell damage or death where it acts as a danger signal. ATP is sensed by the P2X receptors (seven receptors named P2X1-7), mainly expressed by T lymphocytes. We have recently demonstrated that the ATP/P2X7R axis has a key role in cardiac allograft survival in humans and mice. Cardiac allograft vasculopathy (CAV) is a major limiting factor for HT survival; indeed CAV occurs in 50% of HT recipients by 5 years after transplantation and invariably results in allograft failure. CAV is clearly of immunological origin, as syngeneic murine grafts do not develop it. Once CAV occurs, the most definitive treatment is re-transplantation, but survival remains poor. We hypothesize that a single nucleotide polymorphysm (SNP) loss-of-function P2X7R mutation (p.Glu496Ala / c.1513A>C, rs3751143) generates a compensatory upregulation of the other purinergic receptors (P2XsR), thus creating a state of hypersensitivity to eATP. This eATP hypersensitivity results in an abnormal generation of Th1/Th17 cells, that leads to CAV and early cardiac allograft loss. Our study will answer a fundamental question: What is the effect of the P2X7R loss-of-function mutation on the immune system? Our goal is to generate the first targeted-therapy for a selected group of cardiac transplant recipients.

NCT02082821 Cardiac Allograft Vasculopathy
MeSH: Vascular Diseases


Primary Outcomes

Description: nominal change from baseline to 1 year in percent atheroma volume measured by intravascular ultrasound

Measure: Cardiac Allograft Vasculopathy

Time: 1 year

Secondary Outcomes

Description: Death re-transplant biopsy proven acute rejection antibody mediated rejection cellular rejection; treated rejection hemodynamic compromise-associated rejection chronic allograft vasculaopathy at 12-months total atheroma volume; change in average maximal intimal thickness rapid progressive chronic allograft vasculaopathy (change in maximal intimal thickness) ≥0.5 mm in the first year (intravascular ultrasound) histological changes of antibody mediated rejection (Immunohistochemistry).

Measure: Heart Rejection or Patient Death

Time: 6 months; 12 months

Time Perspective: Cross-Sectional

Case-Control


There is one SNP

SNPs


1 rs3751143

We hypothesize that a single nucleotide polymorphysm (SNP) loss-of-function P2X7R mutation (p.Glu496Ala / c.1513A>C, rs3751143) generates a compensatory upregulation of the other purinergic receptors (P2XsR), thus creating a state of hypersensitivity to eATP.

Loss-of-function single nucleotide mutations (SNPs) have been detected for P2X7R gene; particularly the Glu496 to Ala 1513A>C (rs3751143) P2X7R loss-of-function mutation is relatively common (1-3% of individuals are mutated omozygous and 25% are heterozygous).

To test this hypothesis, we will follow two main paths: i) we will evaluate in the CTOT-05 cohort of cardiac transplant recipients the effect of the Glu496 to Ala 1513A>C (rs3751143) P2X7R loss-of-function mutation on clinical end points (development of coronary artery vasculopathy, death, re-transplantation or re-listed for transplantation, any rejection) in the first year post transplant; ii) we will explore in vivo and ex vivo in the CTOT-05 cohort of cardiac transplant recipients the effects of P2X7R loss-of-function mutation on the immune system.



HPO Nodes