miRNA-Based Therapies: Revolutionizing Cancer Treatment Strategies

Micro RNAs (miRNAs) are small non-coding RNA molecules that play a pivotal role in regulating gene expression post-transcriptionally. Since their discovery in 1993, miRNAs have been identified as key players in various cellular processes, including development, proliferation, differentiation, apoptosis, and stress response [1]. In recent years, miRNAs have gained significant attention in the field of cancer research due to their involvement in tumorigenesis, metastasis, and treatment resistance. This article delves into the intricate relationship between miRNAs and cancer, highlighting their potential as therapeutic targets and exploring the challenges and opportunities of utilizing miRNA-based therapies.

miRNAs function by binding to complementary sequences within the 3' untranslated regions (UTRs) of target mRNAs, leading to mRNA degradation or translational repression. This intricate interaction allows miRNAs to fine-tune the expression of numerous genes, ultimately influencing complex cellular processes. The discovery of miRNAs targeting the 5' UTRs and other regions of mRNAs has expanded our understanding of miRNA-mediated gene regulation [2]. One of the key areas of research involving miRNAs is their role in cancer. Their stability in various bodily fluids, such as blood and urine, enables non-invasive testing. Researchers have successfully identified specific miRNA signatures associated with different cancer types, aiding in early diagnosis and accurate prognosis [3].

miRNAs can regulate around 30% of human protein-coding genes, demonstrating their potential impact on various cellular pathways [4]. Dysregulation of miRNAs in cancer can be attributed to epigenetic changes, alterations in miRNA biogenesis, gene polymorphisms, and chromosomal abnormalities. The role of miRNAs in cancer was first observed in chronic lymphocytic leukemia, where the miR-15 and miR-16 clusters were found to be deleted or downregulated, resulting in the overexpression of the anti-apoptotic protein B-cell lymphoma 2 [5]. Further studies have demonstrated that miRNAs are involved in regulating multiple hallmarks of cancer, including cell proliferation, invasion, metastasis, and resistance to chemotherapy.

Harnessing the potential of miRNAs for cancer therapy has gained significant attention. Two main strategies are being explored: inhibiting oncogenic miRNAs to restore tumor suppressing gene expression and restoring tumor suppressing miRNAs to inhibit oncogenes. Various techniques are being developed to achieve these goals. Anti-miRNA Oligonucleotides (AMOs) are single-stranded chemically modified oligonucleotides designed to be complementary to target miRNAs. These molecules bind to mature miRNAs, preventing their interaction with target genes and allowing for the expression of tumor suppressing genes. Modified AMOs like Locked Nucleic Acids (LNAs) and Antisense Phosphorodiamidate Morpholino Oligomers (PMOs) improve stability and efficacy in vivo, showing promise as therapeutic agents [6]. Combining miRNA-based therapy with conventional treatments like chemotherapy and targeted drugs holds great potential. Studies have demonstrated synergistic effects when miRNAs are used in conjunction with chemotherapeutic agents, overcoming drug resistance and increasing treatment efficacy. For instance, miR-34a, known as a tumor suppressor, was successfully combined with chemotherapeutic agents to enhance anti-tumor activity and promote apoptosis in breast cancer cells [7]. The clinical application of miRNA therapeutics is hindered by the absence of a reliable delivery system due to miRNAs' small size and vulnerability to degradation. Current delivery systems include non-viral and viral methods. Non-viral systems use organic, inorganic, or polymer-based carriers. Liposomes, lipid/nucleic acid complexes, are commonly used, particularly cationic liposomes, known for their affinity with cell membranes. Inorganic options include gold nanoparticles and other materials. Polymer-based carriers involve cell-penetrating peptides (CPPs) and synthetic polymers such as PEI, PLGA, and PAMAM dendrimers. Outer membrane vesicles (OMVs) from E. coli and exosomes are also explored as carriers [8, 9]. Viral-based systems use genetically modified viruses. Retroviral vectors can integrate genetic material into host cells during division. Lentiviral vectors can infect both dividing and non-dividing cells, while adenoviruses carry large genes but don't integrate them. Adeno-associated viruses (AAVs) carry miRNA genes and infect various cell types [9, 10]. Challenges include finding systems that efficiently protect miRNAs during delivery, with non-viral methods being less toxic but having lower efficiency and viral vectors facing immunogenicity and cytotoxicity issues. Research continues to refine these systems for effective miRNA-based therapies.

While miRNA-based therapy shows promise, challenges must be addressed for its successful translation into clinical applications. Off-target effects and specificity remain significant concerns. The potential for co-inhibition or co-induction using multiple miRNAs to enhance specificity should be explored. Moreover, selecting the optimal delivery system for miRNAs, which ensures high efficacy and low toxicity, is crucial.

1.      Specificity and Off-Target Effects: Research should focus on minimizing off-target effects and increasing specificity in miRNA-based therapies to enhance their safety and effectiveness.

2.      Combination Therapy Optimization: The potential of miRNA-based therapies in combination with conventional treatments should be further investigated to identify optimal drug combinations and dosages.

3.      Delivery System Development: Developing efficient and targeted delivery systems for miRNAs remains a challenge. Research should aim to design delivery methods that ensure successful and controlled delivery to target cells.

4.      Biomarker Discovery: Identification of specific miRNA signatures associated with different cancer types can lead to the development of personalized treatment strategies.

5.      Clinical Validation: Rigorous pre-clinical and clinical studies are needed to validate the safety and efficacy of miRNA-based therapies, paving the way for their integration into standard cancer treatments.

Ongoing research involves characterizing the roles of specific miRNAs in various cancers and developing innovative delivery systems. Clinical trials are exploring the therapeutic potential of miRNA-based interventions, focusing on safety, efficacy, and patient outcomes. Additionally, understanding the molecular mechanisms underlying miRNA dysregulation in cancer will guide the development of targeted therapies. miRNAs offer immense potential as therapeutic targets in cancer treatment. Their ability to modulate key pathways involved in tumorigenesis makes them attractive candidates for personalized therapy. As research continues to unravel the complex interactions between miRNAs and cancer, addressing challenges related to specificity, delivery, and combination therapies will be essential for harnessing their full potential in clinical applications. The growing body of evidence points towards a future where miRNA-based therapies revolutionize cancer treatment strategies, offering improved outcomes and enhancing the quality of life for cancer patients.

References:

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3.            Ferrara, F., et al., Beyond liquid biopsy: Toward non-invasive assays for distanced cancer diagnostics in pandemics. 2022. 196: p. 113698.

4.            Yang, J., et al., MicroRNA-488: A miRNA with diverse roles and clinical applications in cancer and other human diseases. 2023. 165: p. 115115.

5.            Pekarsky, Y., C.M.J.C.D. Croce, and Differentiation, Role of miR-15/16 in CLL. 2015. 22(1): p. 6-11.

6.            Menon, A., et al., miRNA: A Promising Therapeutic Target in Cancer. Int J Mol Sci, 2022. 23(19).

7.            Grimaldi, A.M., M. Salvatore, and M.J.F.i.o. Incoronato, miRNA-based therapeutics in breast cancer: a systematic review. 2021. 11: p. 668464.

8.            Yan, Y., et al., Non-viral vectors for RNA delivery. 2022. 342: p. 241-279.

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10.          Dasgupta, I., A.J.M. Chatterjee, and protocols, Recent advances in miRNA delivery systems. 2021. 4(1): p. 10.

 By: Muhammad Usman Qamar