Targeting the Root of the Problem: Antisense Oligonucleotide Therapy to Deplete H3 K27M

H3 K27M is a genetic abnormality that plays critical roles in initiating and maintaining growth of diffuse midline glioma (DMG). Most DMG tumors contain histone H3 K27M mutations encoding one of two variants, H3.3 K27M, found across all age groups and DMG tumor locations, and H3.1 K27M, found in the youngest patients with tumors in the pons. We and others used experimental approaches to show that reducing H3 K27M levels delayed or blocked growth of DMG models that were established from patient tumors. However, there are no traditional drugs that directly target H3 K27M.

We plan to optimize use of antisense oligonucleotides (ASOs) to directly target and deplete H3 K27M, block tumor growth and extend survival. ASOs are designed to inhibit a specific gene based on its genetic sequence, although efficiencies are variable. ASO therapies can be delivered into the brain and spinal cord and drive dramatic patient improvements for some neurological diseases.

We completed extensive screening to identify multiple efficient ASOs in cultured DMG cells for each of the common H3 K27M mutations. We now aim to use models of DMG in the brain to gain novel insights that will advance translation to patients including 1) The first in vivo testing of H3.1 K27M ASOs and new more potent H3.3 K27M ASOs, 2) Determine levels of H3 K27M knockdown needed to disrupt different aspects of DMG biology 3) Optimize dosing to block DMG growth and extend survival, 4) Evaluate effects of combined ASO and radiation therapy, and 4) Evaluate ASO-induced changes in the brain that could influence therapeutic response and inform future combination therapies. We are in a unique position to rapidly translate ASOs for DMG into the clinic due to our close collaboration with the St. Jude Pediatric Translational Neuroscience Initiative, which has expertise in clinical and preclinical ASO research, is already delivering ASO therapies to children with neurological diseases and has capacity to produce clinical-grade custom ASOs for patient use.