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Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain cancer that often kills within a year of diagnosis. Surgery is almost impossible because of the tumors鈥� location. Chemotherapy has debilitating side effects. New treatment options are desperately needed.

LaboratoryProfessor Adrian Krainer is best known for his groundbreaking research on antisense oligonucleotides (ASOs)鈥攎olecules that can control protein levels in cells. His efforts led to Spinraza^庐, the first FDA-approved treatment for a deadly neurodegenerative disease called spinal muscular atrophy (SMA).

Following his success with SMA, Krainer started looking into other diseases where ASOs could make a difference. He soon set his sights on DIPG. 鈥淚 was contacted by a neurologist and his friend, who had lost her child to DIPG,鈥� Krainer says. He explains:

鈥淭hey called to ask if what we did for SMA could be applied. Of course, every disease has its own barriers and obstacles, but it seemed doable. We thought it might be possible to develop a therapy.鈥�

Now, Krainer, graduate student Qian Zhang, and their colleagues have developed a potential therapeutic for DIPG using ASO technology similar to that in Spinraza. This new therapy slowed tumor growth, reversed certain changes in cancer cells, and increased survival rates in mice with DIPG. Krainer鈥檚 SMA research laid the foundation for this work.

鈥淲hile working on Spinraza, we learned how to deliver ASOs to the spinal cord and brain,鈥� he explains. 鈥淭hey have long-lasting effects there. So, we knew there was potential for treating other diseases.鈥�

The new ASO drug works by shutting down a mutated protein called H3.3K27M. In DIPG, the dominant mutation blocks closely related proteins from turning many genes on and off. This leads to uncontrolled cell growth鈥攃ancer. When the team used the ASO drug on mice with DIPG, the genes it affected returned to normal. The tumors stopped growing as fast, and the animals lived longer.

鈥淎fter treatment, the cancer looked very different,鈥� says Krainer. 鈥淲e could see a lot fewer proliferating cells, and the tumor cells were differentiating into healthy nerve cells. That tells us DIPG鈥檚 malignant changes are reversible to an extent.鈥�

While hopeful, Krainer says there is still a long way to go before this new therapeutic can begin clinical trials. Additionally, the potential drug would likely need to be paired with another treatment like radiation or immunotherapy.

鈥淐ertainly, we would like this to make it to clinical studies,鈥� he says, 鈥渂ut we didn鈥檛 put all our cards into one approach. We鈥檙e exploring ways to make this even more effective.鈥�

Written by: Nick Wurm, Communications Specialist | wurm@cshl.edu | 516-367-5940

Funding

The Cure Starts Now Foundation, The Simons Foundation, The V Foundation, St. Giles Foundation, National Cancer Institute

Citation

Zhang, Q., et al., 鈥淎ntisense oligonucleotide therapy for H3.3K27M diffuse midline glioma鈥�, Science Translational Medicine, April 12, 2023. DOI: