miR-10b Gene Editing Therapy for Glioblastoma

Malignant glioma, particularly glioblastoma (GBM), remains among the most lethal forms of cancer and represents a significant unmet need in current medicine. The median survival of GBM patients is approximately 15-20 months with highly aggressive standard care, and the five-year survival rate is about 5%. There are no effective therapies for the disease. Over the years, we accumulated evidence that GBM growth and invasiveness are closely regulated by microRNAs, small regulatory molecules that control gene expression and strongly contribute to gliomagenesis. We demonstrated that this class of molecules holds great promise as therapeutic targets for neuro-oncology. Our work led us to focus on miR-10b, a unique growth and invasion-promoting miRNA and common molecular target for GBM in adults (otherwise a highly heterogeneous class of brain malignancies). We identified miR-10b, essential for glioma growth, as a top and common therapeutic target for GBM. Inhibition of miR-10b using different strategies reduced tumor growth in all tested glioma cell and animal models. CRISPR/Cas9 gene-editing of miR-10b emerged as the most potent therapeutic strategy in mice, and it holds great promise for GBM patients. We developed potent and safe lipid nanoparticle (LNP) -based miR-10b editing formulation as a new class of precision medicine for GBM. Our objective is to advance this miR-10b editing drug (called miRTED) into a “first-in-human” clinical trial in subjects with GBM. The Specific Aims of this project are, in UG3 component (Discovery phase): 1) Finalize the efficacy of miRTED administration using diverse orthotopic GBM models, 2) Assess the toxicity and off-target effects of miRTED administration using human and rodent neuroglial cells, brain organoids, and mouse models to establish dosing guidelines, and during UH3 component (Development phase): 3) Partner with BPN team and selected contract research organization to manufacture preclinical and then GMP-grade clinical lots of the LNP, 4) Partner with BPN team and selected contract research organization to conduct IND-enabling mouse toxicology and biodistribution studies, and 5) Finalize the writing and filing of the IND application with the FDA. Due to glioma “addiction” to miR-10b, the new strategy is expected to be highly efficacious for most, if not all, GBM patients despite the heterogeneity of the disease. This approach is principally different from other gene therapies proposed for the GBM- that all target only a subpopulation of patients. It can be used in combination with, or ultimately replace, the current standard care. In addition, the LNP formulations developed in this project could provide a platform technology for precision medicine targeting other tumor vulnerabilities. Notably, the recent success of COVID mRNA vaccines and in vivo gene editing trials provide POCs for the efficacy, safety, and scalability of mRNA/LNPs and CRISPR/Cas9 components in humans. Project Number: 1UG3NS143075-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Anna Krichevsky | Institution: BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, MA | Award Amount: $790,474 | Activity Code: UG3 | Study Section: Special Emphasis Panel[ZRG1 CTH-N (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11264066