A P2X7R Single Nucleotide Mutation Promotes Chronic Allograft Vasculopathy

Completed

Conditions studied: Cardiac Allograft Vasculopathy

In brief

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.

Key facts

Study ID: NCT02082821
Run by: Boston Children's Hospital
People needed: 200
Starts: 2014-01-01
Expected to finish: 2020-12-01
Last updated by the study team: 2021-03-03

Who can join

Age: 18 and older, up to 65. Sex: any. Healthy volunteers: accepted.

You may qualify if…

Male or female cardiac recipients
18-65 years of age
undergoing primary heart transplantation
the graft must be functional at the time of randomization.
patient willing and capable of giving written informed consent for study participation and anticipated to be able to participate in the study for 12 months

You may not qualify if…

Recipient of multi-organ transplants or previously transplanted organs
Patients with donor greater than 65 years
Donor heart cold ischemic time > 6 hours.
Patients who are recipients of ABO incompatible transplants
Patients with platelet count < 50,000/mm3 at the evaluation before transplantation
Patient who have received an unlicensed drug or therapy within one month prior to study entry or if such therapy is to be instituted post-transplantation
Patient with a current severe systemic infection
Patient unable to participate in the study for the full 12-month period
Presence of severe hypercholesterolemia (≥ 350 mg/dL; ≥ 9 mmol/L) or hypertriglyceridemia (≥ 750 mg/dL; ≥ 8.5 mmol/L)
Patients with any past (within the past 5 years) or present malignancy (other than excised basal cell carcinoma)
Females capable of becoming pregnant must have a negative pregnancy test prior to randomization and are required to practice a medically approved method of birth control for the duration of the study and a period of 8 weeks following discontinuation of study medication, even where there has been a history of infertility.
Patients with HIV, hepatitis B or C.

Where it is running

Boston Children's Hospital — Boston, Massachusetts, United States

Full record on ClinicalTrials.gov

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