Implantation of a double allogeneic human engineered tissue graft on damaged heart: insights from the PERISCOPE phase I clinical trial

Abstract

Background: In preclinical studies, the use of double allogeneic grafts has shown promising results in promoting tissue revascularization, reducing infarct size, preventing adverse remodelling and fibrosis, and ultimately enhancing cardiac function. Building upon these findings, the safety of PeriCord, an engineered tissue graft consisting of a decellularised pericardial matrix and umbilical cord Wharton's jelly mesenchymal stromal cells, was evaluated in the PERISCOPE Phase I clinical trial (NCT03798353), marking its first application in human subjects.

Methods: This was a double-blind, single-centre trial that enrolled patients with non-acute myocardial infarction eligible for surgical revascularization. Seven patients were implanted with PeriCord while five served as controls.

Findings: Patients who received PeriCord showed no adverse effects during post-operative phase and one-year follow-up. No significant changes in secondary outcomes, such as quality of life or cardiac function, were found in patients who received PeriCord. However, PeriCord did modulate the kinetics of circulating monocytes involved in post-infarction myocardial repair towards non-classical inflammation-resolving macrophages, as well as levels of monocyte chemoattractants and the prognostic marker Meteorin-like in plasma following treatment.

Interpretation: In summary, the PeriCord graft has exhibited a safe profile and notable immunomodulatory properties. Nevertheless, further research is required to fully unlock its potential as a platform for managing inflammatory-related pathologies.

Funding: This work was supported in part by grants from MICINN (SAF2017-84324-C2-1-R); Instituto de Salud Carlos III (ICI19/00039 and Red RICORS-TERAV RD21/0017/0022, and CIBER Cardiovascular CB16/11/00403) as a part of the Plan Nacional de I + D + I, and co-funded by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER) and AGAUR (2021-SGR-01437).

Keywords: Cardiac regeneration; Cardiac repair; Cardiac tissue engineering; Decellularised tissue; Engineered tissue; Myocardial infarction.

Figure 1

(a) Flowchart of the PERISCOPE clinical trial. (b) Timeline of patient follow-up. (c) Schematic composition of the PeriCord ATMP. (d) cMRI analysis of a Treated patient at Baseline (transmural MI), 3 months (the implanted PeriCord is recognizable, yellow arrows) and at 12 months (PeriCord is integrated in the myocardium and hardly visible). (e) Percentage of activated CCR2^highCX3CR1^mid monocytes and fold change of “non-classical” CD14⁻/CD16⁺ monocyte numbers in peripheral blood of control (n = 5) and treated (n = 7) patients at baseline and 3-, 6- and 9-days post-surgery. (f) CCR2 and CX3CR1 surface expression in peripheral blood monocytes. (g) Circulating levels of monocyte chemoattractants MCP-1/CCL2, MCP-2/CCL8 and MCP-4/CCL13 and (h) Meteorin-like (Metrnl) in plasma of control (n = 5) and treated (n = 7) patients at baseline and 3-, 6- and 9-days post-surgery. Statistical differences are indicated for ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001 according to paired Two-way ANOVA. Time-dependent differences are indicated in black and blue for control and treated patients, respectively. MFI, median fluorescence intensity.