Pharmacokinetics and Pharmacodynamics of Bioengineered miR‐34a Prodrug

• DOI: 10.1096/fasebj.30.1_supplement.712.3
• Publication Date: 2023-11-26T16:48:44Z
• Authors: Pui Yan Ho; Wei‐Peng Wang; Qiu‐Xia Chen; Balasubrahmanyam ...; Patrick A. Limbach; Mei‐Mei Li; Joseph Lionel Jilek; Jing‐Xin Qiu; Hong‐Jian Zhang; Tianhong Li; Theodore Wun; Ralph DeVere White; Kit S Lam; Ai‐Ming Yu

The complexity of cancer has been demonstrated to closely align with an alteration in gene expression profiles. Dysregulated miRNAs control many fundamental biological processes including tumor progression through the suppression of multiple target genes, suggesting the development of miRNA based therapy. Recently we have developed a novel approach to biosynthesize chimeric tRNA/mir‐34a agents in Escherichia coli on a large scale, which may act as a prodrug for miR‐34a replacement therapy. In this study, we aimed to define the pharmacokinetics and pharmacodynamics of bioengineered miR‐34a prodrug. We found that miR‐34a prodrug is susceptible to Dicer and other RNases (e.g., RNase A and Angiogenin), yet protected from degradation when formulated with in vivo‐jetPEI. Higher levels of accumulation were seen in mouse liver and lung for in vivo‐jetPEI formulated miR‐34a prodrug administered intravenously. We further monitored the metabolic fate of tRNA/mir‐34a in human carcinoma cells through deep sequencing and qPCR analyses, and our data demonstrated a precise production of mature miR‐34a from the prodrug. As a result, miR‐34a prodrug caused a significant downregulation of miR‐34a target genes (e.g., CDK6, MET, SIRT1) in human cancer cells and a sharp reduction of tumor growth in A549 xenograft mouse models. In addition, we examined the acute effects of biologic miR‐34a agents by analyzing blood chemistry profiles and IL‐6 levels in mouse models, which showed no signs of acute toxicity. Therefore, we illustrate the fate, efficacy and safety of recombinant miR‐34a prodrug that would exemplify the promise of bioengineered miRNA agents in research and development.