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Antisense oligonucleotide therapy for H3.3K27M diffuse midline glioma
Qian Zhang1,2, Lucia Yang1,3,4, Ying Hsiu Liu1
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA.
Science Translational Medicine
|April 12, 2023
Summary
A new antisense oligonucleotide therapy effectively targets the H3.3K27M mutation in diffuse midline gliomas (DMG), a pediatric brain tumor. This treatment reduced tumor growth and improved survival in preclinical models by restoring normal epigenetic marks.
Area of Science:
- Oncology
- Genetics
- Epigenetics
Background:
- Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPG), are aggressive pediatric brain tumors with poor prognoses.
- Most DMGs harbor a specific mutation (K27M) in the H3.3 gene, leading to aberrant epigenetic changes driving tumor formation.
Purpose of the Study:
- To develop and evaluate an antisense oligonucleotide (ASO) therapy targeting the H3.3K27M mutation in DMGs.
- To assess the efficacy of ASO treatment in preclinical DMG models.
Main Methods:
- Systematic screening of 2'-O-methoxyethyl phosphorothioate antisense oligonucleotides (ASOs) targeting H3-3A mRNA.
- Testing of a lead ASO in patient-derived neurospheres and two mouse models of DIPG.
Main Results:
- The lead ASO successfully reduced H3-3A mRNA and H3.3K27M protein, restoring H3K27 trimethylation.
- ASO treatment in mouse models decreased tumor growth, promoted neural differentiation, and increased survival.
Conclusions:
- The H3.3K27M oncohistone is crucial for DMG maintenance.
- ASO therapy targeting H3.3K27M demonstrates preclinical efficacy, offering a potential new treatment strategy for diffuse midline gliomas.
