Al-Saadi Jonathan, Waldén Mathias, Sandell Mikael, Sohlmér Jesper, Grankvist Rikard, Friberger Ida, Andersson Agneta, Carlsten Mattias, Chien Kenneth, Lundberg Johan, Witman Nevin, Holmin Staffan
Department of Clinical Neuroscience, Karolinska Institute, Tomtebodavägen 18A, 171 65 Stockholm, Sweden.
Department of Neuroradiology, Karolinska University Hospital, 171 64 Stockholm, Sweden.
Mol Ther Methods Clin Dev. 2024 Feb 27;32(2):101225. doi: 10.1016/j.omtm.2024.101225. eCollection 2024 Jun 13.
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 -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 . 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.
心力衰竭预后较差，且尚无治愈性治疗方法。临床试验正在研究基于基因和细胞的疗法以改善心脏功能。将这些疗法安全有效地输送到实体器官具有挑战性。在此，我们证明了使用血管内心肌内递送方法在猪体内安全施用mRNA药物产品并进行细胞移植程序的可行性。使用血管壁（TW）装置，我们将化学修饰的mRNA（modRNA）和表达血管内皮生长因子A（VEGF-A）的mRNA增强间充质基质细胞直接递送至心脏。我们监测并绘制了这种方法的细胞分布、蛋白质表达和安全耐受性。通过TW装置以不同流速和细胞浓度递送modRNA增强细胞对细胞活力和蛋白质表达的影响微乎其微。给药后至少3天内在心肌中发现植入的细胞，无需使用免疫调节，对组织完整性的影响最小。最后，与在盐溶液中递送的modRNA相比，我们使用细胞介导的modRNA递送系统可使心脏中VEGF-A的蛋白质表达增加500倍以上。最终，该方法为未来开创心脏病新疗法的研究铺平了道路。
