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

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy-Methods & Clinical Development Pub Date : 2024-02-27 DOI:10.1016/j.omtm.2024.101225

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

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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 -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.

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通过血管内移植 mRNA 增强间充质基质细胞，猪心脏的治疗性蛋白表达效果更佳

心力衰竭的预后很差，目前尚无根治的疗法。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是一项挑战。在这里，我们展示了使用血管内心肌内给药方法在猪体内安全给药 mRNA 药物产品和进行细胞移植手术的可行性。我们使用血管壁（TW）装置将化学修饰的 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输送到心脏。我们对这种方法的细胞分布、蛋白表达和安全耐受性进行了监测和绘图。通过 TW 装置输送 modRNA 增强细胞，不同的流速和细胞浓度对细胞存活率和蛋白表达影响不大。植入的细胞在给药后至少 3 天内仍在心肌内，无需使用免疫调节，对组织完整性的影响极小。最后，与在生理盐水中递送 modRNA 相比，我们利用细胞介导的 modRNA 递送系统可使心脏中 VEGF-A 蛋白表达量增加 500 倍以上。最终，这种方法为未来研究开创心脏疾病的新疗法铺平了道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.90

自引率

4.30%

发文量

163

审稿时长

12 weeks

期刊介绍： The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.