NXL-004: A novel trans-differentiation therapy for glioblastoma treatment.

e14020 Background: Gliomas, tumors originating from glial cells in the brain and spinal cord, constitute 80% of all malignant primary tumors affecting the central nervous system, with glioblastomas (GBM) as the most prevalent and aggressive subtype accounting for approximately 60% of cases. Current treatment options for GBM, including surgery, radiation therapy, and chemotherapy, have limited effectiveness in improving patient outcomes. Therefore, there is a critical need for more effective therapeutic approaches to treat GBM. Methods: We present NXL-004, an adeno-associated virus (AAV) vector delivering the neural transcription factor NeuroD1 directly into GBM tumor cells, as a novel therapy for GBM. Various GBM models were utilized to investigate NXL-004 treatment for GBM, including U87 intracranial and subcutaneous models in mice, PDX model and GBM organoid. Results: The results demonstrated that NXL-004 significantly reduced tumor size compared to the control group; (D) NXL-004 exhibited a significant effect in prolonging the survival of the GBM mouse model. The median survival of mice treated with NXL-004 was 34 days post tumor implantation, whereas the control group had a median survival of only 16 days. Conclusions: Preclinical studies of NXL-004 have demonstrated that this intervention effectively reprograms tumor cells, downregulating glial cell- and tumor-related gene expression, while concurrently upregulating neuron-related gene expression. The induced differentiation towards non-dividing neurons results in significant inhibition of tumor cell proliferation, substantial reductions in tumor volume and prolonged survival in GBM-bearing mice. Additionally, NXL-004 has exhibited a favorable safety profile in toxicity studies in rats and non-human primates. These preclinical outcomes paved the way for subsequent clinical evaluation, representing a potential breakthrough in GBM treatment.