Synthetic miR-34a against solid tumours: a predictable failure

Mockly, Sophie; Seitz, Hervé

doi:10.1038/s41416-022-02123-8

Cited by 6 publications

(3 citation statements)

References 12 publications

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“…Until now, endeavours to employ modified miR-34a as a therapeutic agent have encountered setbacks in clinical trials 66 . These failures have been attributed to issues of non-specificity and high drug dosages, which can trigger immunogenic responses 67 . By tailoring miRNA- based drugs based on known structural information, we may have the potential to create more effective treatments characterised by a reduced immunogenic profile and a more selective targeting approach.…”

Section: Discussionmentioning

confidence: 99%

Biophysics of microRNA-34a targeting and its influence on down-regulation

Sweetapple,

Kosek,

Banijamali

et al. 2024

Preprint

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microRNAs (miRNAs) regulate target mRNA expression post-transcriptionally through their association with Argonaute 2 (AGO2) proteins. Predicting the efficiency of mRNA repression by miRNA has been limited by our comprehension of the structure-function relationship within miRNA binding sites. Using a combination of EMSA, luciferase reporter assays, and structural probing, we investigated the interaction between the human tumour suppressor miR-34a and 12 mRNA targets. Comparison of direct RNA:RNA interactions and those within the functional AGO2 protein revealed that the isolated mRNA:miRNA duplex serves as a strong predictor for duplex affinity and structure within AGO2. Our findings reveal that AGO2 has a bidirectional capacity to modulate affinity; weakening tight RNA:RNA binders while strengthening weak ones. We identified three distinct structural groups that form upon miR-34a binding and reveal a novel structural group that exhibits a guide strand bulge. MD simulations indicate a conceivable fit of this miRNA-bulge structure within AGO2. Our results demonstrate that the structural characteristics of mRNA:miRNA duplexes could serve as contributing determinants of repression efficacy.

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Section: Discussionmentioning

confidence: 99%

Biophysics of microRNA-34a targeting and its influence on down-regulation

Sweetapple,

Kosek,

Banijamali

et al. 2024

Preprint

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“…Allowing the mutation of miRNA genes, or of their binding sites in target RNAs, or both of them simultaneously in a compensatory manner, this technique should allow to disrupt and restore miRNA/target interactions on demand in a complete in vivo setting. The analysis of physiological phenotypes controlled by individual interactions is much needed, as exemplified by the frequent misannotation of the biological roles of miRNA/target interactions when it is based on extrapolated ex vivo or in silico analyses [Mockly and Seitz, 2019 ; Mockly and Seitz, 2023].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of microRNA variant maturation prior to genome edition

Busseau

Mockly

Houbron

et al. 2022

Preprint

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Assessment of the functionality of individual microRNA/target sites is a crucial issue. Genome editing techniques should theoretically permit a fine functional exploration of such interactions, allowing the mutation of microRNAs or individual binding sites in a complete in vivo setting, therefore abrogating or restoring individual interactions on demand. A major limitation to this experimental strategy is the influence of microRNA sequence on its accumulation level, which introduces a confounding effect when assessing phenotypic rescue by compensatorily mutated microRNA and target site. Here we describe a simple assay to identify microRNA variants most likely to accumulate at wild-type levels even though their sequence has been mutated. In this assay, quantification of a reporter construct in cultured cells predicts the efficiency of an early biogenesis step, the Drosha-dependent cleavage of microRNA precursors, which appears to be a major determinant of microRNA accumulation in our variant collection. This system allowed the generation of a mutant Drosophila strain expressing a bantam microRNA variant at wild-type levels.

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“…Other authors have associated miR-34a with Acute Respiratory Distress Syndrome [80], an inflammatory disorder resulting in rare fatal irAEs such as pneumonitis or respiratory failures [81], or other irAEs. Finally, further evidence of the need to maintain low miR-34a levels is demonstrated by the early closure of the Phase 1 study of MRX34, a liposomal mimic of miR-34a, in patients with advanced solid tumors, due to the death of several patients [82,83].…”

Section: Mirnas That Regulate Immune-related Adverse Events (Iraes)mentioning

confidence: 99%

miRNAs Related to Immune Checkpoint Inhibitor Response: A Systematic Review

García-Giménez,

Saadi,

Ortega

et al. 2024

IJMS

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The advent of immune checkpoint inhibitors (ICIs) has represented a breakthrough in the treatment of many cancers, although a high number of patients fail to respond to ICIs, which is partially due to the ability of tumor cells to evade immune system surveillance. Non-coding microRNAs (miRNAs) have been shown to modulate the immune evasion of tumor cells, and there is thus growing interest in elucidating whether these miRNAs could be targetable or proposed as novel biomarkers for prognosis and treatment response to ICIs. We therefore performed an extensive literature analysis to evaluate the clinical utility of miRNAs with a confirmed direct relationship with treatment response to ICIs. As a result of this systematic review, we have stratified the miRNA landscape into (i) miRNAs whose levels directly modulate response to ICIs, (ii) miRNAs whose expression is modulated by ICIs, and (iii) miRNAs that directly elicit toxic effects or participate in immune-related adverse events (irAEs) caused by ICIs.

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Synthetic miR-34a against solid tumours: a predictable failure

Cited by 6 publications

References 12 publications

Biophysics of microRNA-34a targeting and its influence on down-regulation

Biophysics of microRNA-34a targeting and its influence on down-regulation

Evaluation of microRNA variant maturation prior to genome edition

miRNAs Related to Immune Checkpoint Inhibitor Response: A Systematic Review

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