NF1 mutation-induced neuronal hyperexcitability drives murine optic glioma growth and can be targeted by lamotrigine treatment
Title: Treating Low-Grade Optic Pathway Glioma by Inhibiting Neuronal Activity
Introduction: Optic pathway glioma (OPG) is a low-grade glioma commonly found in children with neurofibromatosis type 1 (NF1). NF1 is a common neurocutaneous syndrome with an incidence of approximately 1⁄3000. Although OPG is a low-grade tumor, it can lead to serious complications such as vision loss, severely impacting the quality of life of affected children. Current treatments, including chemotherapy and targeted therapies, have limited efficacy and adverse effects. This study found that NF1 mutations can lead to increased excitability and secretion of midkine protein in retinal ganglion cells (RGCs), promoting OPG tumor growth. The antiepileptic drug lamotrigine (LTR) can inhibit RGC excitability, decrease midkine expression, and subsequently suppress OPG tumor progression.
Source of the Paper: This research was conducted by Corina Anastasaki et al. from Washington University in St. Louis, and the findings were published in the journal Neuro-Oncology in 2024.
Research Methods and Key Findings:
- Demonstrated the necessity and sufficiency of midkine for OPG growth
a) Knocking out the midkine gene in mice or knocking down midkine expression in RGCs via viral vectors significantly reduced OPG tumor proliferation and immune cell infiltration but did not affect the activity of the growth factor Ras.
b) Introducing the midkine gene via adeno-associated virus increased midkine levels, inflammatory cytokines, and tumor proliferation in the optic nerves of OPG mouse models.
- Revealed that NF1 mutations lead to increased RGC excitability and midkine expression
The researchers generated mouse models with five different NF1 mutations. In mice with NF1 mutations that induced OPG growth (OPG group), RGCs exhibited increased excitability and midkine overexpression. In contrast, RGC excitability and midkine expression levels were unchanged in mice with NF1 mutations that did not lead to OPG growth (non-OPG group). These results suggest that different NF1 mutation sites determine the differences in RGC activity and midkine expression, thereby influencing the risk of OPG occurrence.
- Lamotrigine specifically inhibits midkine expression in NF1-mutant RGCs
Drug screening on NF1-mutant RGCs revealed that the antiepileptic drugs lamotrigine and valproic acid could reduce midkine expression and excitability in NF1-mutant RGCs to normal levels, while other antiepileptic drugs increased midkine expression.
- Lamotrigine long-term inhibition of OPG tumor growth
a) Administration of lamotrigine before OPG formation (4-8 weeks of age) led to long-term (3 months after treatment cessation) inhibition of OPG growth and increased retinal nerve fiber layer thickness.
b) Treatment with lamotrigine after OPG formation (12 weeks of age) also resulted in long-term suppression of OPG proliferation.
- Clinically relevant doses of lamotrigine effectively inhibit OPG growth
When different OPG mouse models were treated with lamotrigine at doses of 2.5-7.5 mg/kg (within the clinical range for children) for 4 weeks, all doses effectively reduced midkine levels in OPG, inhibited tumor proliferation, and improved pathological changes in the retinal nerve fiber layer.
Conclusion: This study elucidated that NF1 mutations leading to increased RGC excitability and midkine secretion are key drivers of OPG development. Lamotrigine can specifically inhibit this process, leading to long-term suppression of OPG growth, and remains effective at clinical doses. These findings provide strong evidence for lamotrigine as a potential new therapeutic target for OPG and lay the foundation for future clinical translation.