Endovascular transplantation of mRNA-enhanced mesenchymal stromal cells results in superior therapeutic protein expression in swine heart

Jonathan Al-Saadi; Mathias Waldén; Mikael Sandell; Jesper Sohlmér; Rikard Grankvist; Ida Friberger; Agneta Andersson; Mattias Carlsten; Kenneth Chien; Johan Lundberg; Nevin Witman; Staffan Holmin

doi:10.1016/j.omtm.2024.101225

Endovascular transplantation of mRNA-enhanced mesenchymal stromal cells results in superior therapeutic protein expression in swine heart

Mol Ther Methods Clin Dev. 2024 Feb 27;32(2):101225. doi: 10.1016/j.omtm.2024.101225. eCollection 2024 Jun 13.

Authors

Jonathan Al-Saadi^{1

2

3}, Mathias Waldén¹, Mikael Sandell^{1

3

4}, Jesper Sohlmér⁵, Rikard Grankvist¹, Ida Friberger¹, Agneta Andersson⁶, Mattias Carlsten^{6

7}, Kenneth Chien⁵, Johan Lundberg^{1

2

3}, Nevin Witman¹, Staffan Holmin^{1

2

3}

Affiliations

¹ Department of Clinical Neuroscience, Karolinska Institute, Tomtebodavägen 18A, 171 65 Stockholm, Sweden.
² Department of Neuroradiology, Karolinska University Hospital, 171 64 Stockholm, Sweden.
³ MedTechLabs, Stockholm, Sweden.
⁴ Division of Micro and Nanosystems, KTH Royal Institute of Technology, Malvinas väg 10, 114 28 Stockholm, Sweden.
⁵ Department of Cell and Molecular Biology, Karolinska Institute, Solnavägen 9, 171 65 Stockholm, Sweden.
⁶ Department of Medicine, Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.
⁷ Center for Cell Therapy and Allogeneic Stem Cell Transplantation, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Heart failure has a poor prognosis and no curative treatment exists. Clinical trials are investigating gene- and cell-based therapies to improve cardiac function. The safe and efficient delivery of these therapies to solid organs is challenging. Herein, we demonstrate the feasibility of using an endovascular intramyocardial delivery approach to safely administer mRNA drug products and perform cell transplantation procedures in swine. Using a trans-vessel wall (TW) device, we delivered chemically modified mRNAs (modRNA) and mRNA-enhanced mesenchymal stromal cells expressing vascular endothelial growth factor A (VEGF-A) directly to the heart. We monitored and mapped the cellular distribution, protein expression, and safety tolerability of such an approach. The delivery of modRNA-enhanced cells via the TW device with different flow rates and cell concentrations marginally affect cell viability and protein expression in situ. Implanted cells were found within the myocardium for at least 3 days following administration, without the use of immunomodulation and minimal impact on tissue integrity. Finally, we could increase the protein expression of VEGF-A over 500-fold in the heart using a cell-mediated modRNA delivery system compared with modRNA delivered in saline solution. Ultimately, this method paves the way for future research to pioneer new treatments for cardiac disease.

Keywords: cardiology; cell transplantation; endovascular intervention; endovascular intramyocardial transplantation; heart failure; mRNA drug products; mesenchymal stromal cells; modRNA; trans-vessel wall device; vascular endothelial growth factor.