Trials and Tribulations of MicroRNA Therapeutics

Abstract

The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings.

Decoding the secrets of longevity: unraveling nutraceutical and miRNA-Mediated aging pathways and therapeutic strategies

“…Additionally, some have been discontinued due to concerns about toxicity. These obstacles underscore the need to overcome current obstacles to fully realize the potential of miRNA-based treatments in clinical settings ( Seyhan, 2024 ). Currently, no miRNAs are undergoing clinical trials for longevity enhancement.…”

Harnessing Extracellular microRNAs for Diagnostics and Therapeutics in Acute Systemic Inflammation

“…Lastly, lipid-based chaperones are commercially available, relatively inexpensive, and have been used in clinical trials, but they are not without risks [ 90 , 91 , 92 ]. Some authors have even postulated the ability to deliver miRNA therapeutics orally, given the stability that these delivery mechanisms provide [ 93 ]. Each method has advantages and disadvantages, but they all focus on delivery of the miRNA-based therapeutic into the target cell.…”

“…For example, miR-34a administered through liposomal injection has been evaluated for the treatment of solid tumors, but progress has been slowed due to patient safety concerns [ 92 , 96 ]. As a drug class, miRNA therapeutics have not yet advanced beyond phase two trials, and miRNA-based therapeutics for acute inflammatory pathologies remain primarily preclinical [ 86 , 93 , 97 ].…”

Integrated miRNA–mRNA Analysis Reveals Critical miRNAs and Targets in Diet-Induced Obesity-Related Glomerulopathy

“…So-called “microRNAs” (miRNAs) are short, non-coding RNAs (ncRNAs) that play principal roles in normal physiological processes as well as in the development of diseases [ 9 ]. For example, miRNAs play critical roles in modulating gene expressions implicated in cell differentiation, growth/proliferation, migration, metabolism, and defense and exhibit tissue-specific patterns [ 10 ].…”

“…Indeed, consistent data suggest that the dysregulation of specific ncRNAs contributes to cancer development by upregulating or silencing target genes. Epigenetic signatures have been demonstrated to be characteristic of many cancers, and miRNAs also appear to be independent prognostic factors of the disease [ 8 , 10 ]. Also, some miRNAs have been identified as being involved in kidney diseases.…”