MRX34 / Synlogic - LARVOL DELTA

From Laboratory to Clinic: Translational Challenges, Lessons, and Future Strategies for microRNA Delivery Systems. (PubMed, Curr Drug Deliv) - "This review critically evaluates representative clinical and advanced translational programs, including Miravirsen, MRX34, Cobomarsen, Remlarsen, RGLS4326, and farabursen (RGLS8429), to compare molecular designs, delivery approaches, development outcomes, and translational bottlenecks. Drawing on these lessons, we propose a Four-Pillar Framework integrating Delivery Systems, Immune Safety, CMC and Manufacturing Readiness, and biomarker-guided Clinical Design. Together, these principles support coordinated optimization across biological, pharmaceutical, and clinical dimensions rather than isolated improvement of individual delivery parameters."

Journal

Nanocarrier mediated microRNA delivery for oral squamous cell carcinoma a scoping review of delivery architecture preclinical efficacy and translational barriers. (PubMed, Discov Nano) - "Nanocarrier-mediated miRNA delivery shows encouraging preclinical evidence in OSCC, largely from immunodeficient xenograft systems, but mechanistic heterogeneity, immunogenicity and the absence of standardized preclinical models impede clinical translation. Future development may benefit from prioritizing ionizable lipid formulations with defined immunocompatibility profiles, biomarker-stratified patient selection and orthotopic immune-competent OSCC models. Clinical trial number Not applicable."

Journal • Preclinical • Review • Oncology • Oral Cancer • Squamous Cell Carcinoma • MIR145 • MIR199A • MIR199A1 • MIR200C • MIR34A

Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours. (PubMed, Br J Cancer) - P1 | "MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy."

Clinical • Journal • P1 data • Fatigue • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Pain • Solid Tumor

RNA Therapeutics in Viral Infections and Cancer: Mechanisms, Challenges, and Prospects: A Review. (PubMed, Pharmaceutics) - "Approaches include targeting viral transcripts directly (e.g., siRNAs against HBV surface antigen) or host factors critical for viral replication (e.g., anti-miR-122 miravirsen for HCV)...These include TargomiR (a miR-16 mimic for mesothelioma), cobomarsen (an anti-miR-155 for lymphomas), and MRX34 (a miR-34a mimic for various solid tumours)...Despite promising preclinical results, clinical translation has been hampered by issues like insufficient delivery efficiency to human tumours, toxicity, and the complex, interconnected regulatory networks of miRNAs, which can lead to unpredictable off-target effects. While RNA therapeutics hold immense promise, overcoming delivery barriers and enhancing understanding of RNA regulatory networks are essential for future success."

Journal • Review • Breast Cancer • Hematological Malignancies • Hepatitis B • Human Immunodeficiency Virus • Infectious Disease • Lymphoma • Mesothelioma • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor • BCL2 • KRAS • MIR122 • MIR155 • MIR16 • MIR221 • MIR34A

Therapeutic microRNAs: Mechanisms, Delivery, and Clinical Translation in Oncology. (PubMed, Int J Mol Sci) - "Early clinical programs such as MRX34, TargomiR/MesomiR-1, and cobomarsen, together with experience from non-oncology indications, illustrate both opportunities and practical constraints on tolerability and regimen optimization. We conclude with pragmatic priorities for the field, including standardized analytics for isoforms and target engagement, PK/PD- and biomarker-guided dose selection, and rational combination strategies to safely integrate miRNA-based interventions into precision oncology."

Journal • Review • Oncology

Nanotechnology-enabled miRNA delivery systems next-generation molecular strategies in cancer therapy. (PubMed, Biochem Biophys Res Commun) - "We conclude with a concise roadmap that prioritizes platform selection for near-term translation and integration with tumor-specific miRNA signatures to advance personalized therapy. Our translation-first synthesis links barriers to design solutions (pKa-tuned LNPs; exosome-mimetic/hybrid vesicles) and highlights AI/ML-guided formulation; lessons from MRX34/TargomiRs inform safety, scalability, and CMC-together yielding a practical 24-36-month roadmap toward clinical readiness, with functionalized LNPs best positioned for near-term translation."

Journal • Review • Oncology

Targeted Delivery of miR-34a via Anti-CD47 Antibody Conjugates for Enhanced Cancer Immunotherapy in Triple Negative Breast Cancer. (PubMed, Small) - "However, the clinical translation of miR-34a has been hindered by challenges such as poor stability, inefficient cytoplasmic delivery, and immune-related toxicities, as evidenced by the failure of MRX34 in trials...This dual mechanism promoted macrophage phagocytosis, enhanced CD8+ T-cell activation, and induced apoptosis, resulting in significant tumor inhibition without systemic toxicity. These findings demonstrate the transformative potential of aCD47-C-miR34a in overcoming TNBC's oncogenic and immune-evasive mechanisms, paving the way for innovative treatments in TNBC and other heterogeneous, aggressive cancers."

IO biomarker • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • ER • HER-2 • MIR34A • PD-L1 • PGR

Oligonucleotide-Based Modulation of Macrophage Polarization: Emerging Strategies in Immunotherapy. (PubMed, Immun Inflamm Dis) - "Optimizing delivery platforms, enhancing molecular stability, and rigorous safety profiling are critical. Integration with emerging modalities-such as engineered CAR‑macrophages-will enable precise, disease‑specific interventions, and advance oligonucleotide‑guided macrophage modulation toward clinical translation."

Journal • Review • Infectious Disease • Oncology

MicroRNAs and Long Non-coding RNAs as Novel Targets in Anti-cancer Drug Development. (PubMed, Curr Pharm Biotechnol) - "In this chapter, the strategies and importance of targeting microRNAs and long non-coding RNAs will be described, along with the clinical studies that involve microRNA-based cancer therapeutics and preclinical studies that involve long non-coding RNA-based therapeutics. Finally, the delivery strategies that have great importance in the effective delivery of the non-coding RNA-based cancer therapeutics, hence the therapy's effectiveness, will be described."

Journal • Oncology

Functional and Clinical Significance of Dysregulated microRNAs in Liver Cancer. (PubMed, Cancers (Basel)) - "Clinical treatment drugs have been developed based on miR-34 and miR-122 (MRX34 and Miravirsen, respectively), but their side effects have not yet been overcome. Future research is needed to address these weaknesses and establish a feasible microRNA-based treatment strategy for liver cancer."

Clinical • Journal • Review • Gastrointestinal Cancer • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Oncology • Solid Tumor • MIR122 • MIR21 • MIR214 • MIR34A

MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic. (PubMed, Front Cell Dev Biol) - "We shall briefly discuss potential reasons behind the failure of the first-in-class clinical trial of MRX34, a liposomal miR-34a mimic. Finally, we offer several clinical settings where miR-34a can potentially be deployed to therapeutically target CSCs and advanced, therapy-resistant, and p53-mutant tumors in order to overcome therapy resistance and curb tumor relapse."

Cancer stem cells • IO biomarker • Journal • Review • Oncology • BCL2 • CD44 • MIR34A • MYC • TP53

Down-regulation of target gene expression in human white blood cells (hWBCs) by MRX34, a liposomal miR-34 mimic: Next generation sequencing (NGS) results from a first-in-human trial of microRNA cancer therapy (ESMO 2016) - P1; "This NGS analysis of hWBC samples from patients treated with MRX34 in a first-in-human clinical trial of miRNA cancer therapy showed dosedependent modulation of expression for validated and predicted miR-34a target genes, including key oncogenes. Our work suggests that MRX34 effectively delivers active miR-34a mimics to hWBCs in patients with cancer, and provides a potentially useful method to evaluate biomarkers of response to MRX34 therapy."

Biomarker • Cancer stem cells • Clinical • Tumor microenvironment • Biosimilar • Oncology

Shousha, Naglaa Zayed, Mahmoud N El-Rouby, Ahmed O Kaseb, Ashraf - "...Ahmed O. Kaseb...Veliparib Hydrophobic bile acids, such as deoxycholic acid (DCA), are know to modulate the expression of several apoptosis-related proteins, including c-Jun N-terminal kinase (JNK), leading to cell death. In addition, microRNAs (miRNAs or miRs) are being increasingly implicated in cell death and in the pathogenesis of human liver diseases."

Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance. (PubMed, Cells) - "Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use."

Journal • Review • CD8 • IL6

Expanding the Biotherapeutics Realm via miR-34a: "Potent Clever Little" Agent in Breast Cancer Therapy. (PubMed, Curr Pharm Biotechnol) - "These findings suggest a robust cause for developing miR-34a as a therapeutic agent to target BC. In that scenario, miR-34a is strongly useful to introduce new therapeutic goals for BC. Moreover, this review aims to confirm the signal pathways, therapeutic and diagnostic values of miR- 34a in BC and beyond."

IO Biomarker • Journal

MicroRNA-34 family: a potential tumor suppressor and therapeutic candidate in cancer. (PubMed, J Exp Clin Cancer Res) - P1; "...Along with the application of MRX34, the first tumor-targeted microRNA drug which based on miR-34a mimics, on phase I clinical trial (NCT01829971), the significance of miR-34 is increasingly recognized...Furthermore, its potential role as a microRNA therapeutic candidate is also discussed. Notwithstanding some obstacles existed, the extensive application prospect of miR-34 on oncotherapy cannot be neglected."

Journal • Review