Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Schwannoma gene therapy by adeno-associated virus delivery of the pore-forming protein Gasdermin-D

Cancer Gene Therapy volume 26, pages 259–267 (2019)Cite this article

Subjects

A Correction to this article was published on 06 May 2019

This article has been updated

Abstract

Schwannomas are peripheral nerve sheath tumors associated with three genetically distinct disease entities, namely sporadic schwannoma, neurofibromatosis type-2, and schwannomatosis. Schwannomas are associated with severe disability and in cases lead to death. The primary treatment is operative resection that itself can cause neurologic damage and is at times contra-indicated due to tumor location. Given their homogenous Schwann-lineage cellular composition, schwannomas are appealing targets for gene therapy. In the present study, we have generated an adeno-associated serotype 1 virus (AAV1)-based vector delivering N-terminal of the pyroptotic gene Gasdermin-D; (GSDMDNterm) under the control of the Schwann-cell specific promoter, P0. we have demonstrated that AAV1-P0-GSDMDNterm injection into intra-sciatic schwannomas reduces the growth of these tumors and resolves tumor-associated pain without causing neurologic damage. This AAV1-P0-GSDMDNterm vector holds promise for clinical treatment of schwannomas via direct intra-tumoral injection.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

  • 06 May 2019

    The original version of this Article contained an error in the spelling of the author Ahmed Abdelanabi, which was incorrectly given as Abdelanabi Ahmed. This has now been corrected in both the PDF and HTML versions of the Article.

References

  1. Evans DG. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. 2009;4:16.

    Article  Google Scholar 

  2. Antinheimo J, Sankila R, Carpen O, Pukkala E, Sainio M, Jaaskelainen J. Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology. 2000;54:71–6.

    Article  CAS  Google Scholar 

  3. Lu-Emerson C, Plotkin SR. The neurofibromatoses. Part 2: NF2 and schwannomatosis. Rev Neurol Dis. 2009;6:E81–6.

    PubMed  Google Scholar 

  4. Carlson ML, Jacob JT, Habermann EB, Glasgow AE, Raghunathan A, Link MJ. Malignant peripheral nerve sheath tumors of the eighth cranial nerve arising without prior irradiation. J Neurosurg. 2016;125:1120–9.

    Article  Google Scholar 

  5. Yamanaka R, Hayano A. Radiation-induced malignant peripheral nerve sheath tumors: a systematic review. World Neurosurg. 2017;105:961–70 e8.

    Article  Google Scholar 

  6. Wong HK, Lahdenranta J, Kamoun WS, Chan AW, McClatchey AI, Plotkin SR, et al. Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors. Cancer Res. 2010;70:3483–93.

    Article  CAS  Google Scholar 

  7. Prabhakar S, Brenner GJ, Sung B, Messerli SM, Mao J, Sena-Esteves M, et al. Imaging and therapy of experimental schwannomas using HSV amplicon vector-encoding apoptotic protein under Schwann cell promoter. Cancer Gene Ther. 2010;17:266–74.

    Article  CAS  Google Scholar 

  8. Prabhakar S, Taherian M, Gianni D, Conlon TJ, Fulci G, Brockmann J, et al. Regression of schwannomas induced by adeno-associated virus-mediated delivery of caspase-1. Hum Gene Ther. 2013;24:152–62.

    Article  CAS  Google Scholar 

  9. He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 2015;25:1285–98.

    Article  CAS  Google Scholar 

  10. Kayagaki N, Stowe IB, Lee BL, O'Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526:666–71.

    Article  CAS  Google Scholar 

  11. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5.

    Article  CAS  Google Scholar 

  12. Lamkanfi M. Emerging inflammasome effector mechanisms. Nat Rev Immunol. 2011;11:213–20.

    Article  CAS  Google Scholar 

  13. Broz P. Immunology: caspase target drives pyroptosis. Nature. 2015;526:642–3.

    Article  CAS  Google Scholar 

  14. Hung G, Li X, Faudoa R, Xeu Z, Kluwe L, Rhim JS, et al. Establishment and characterization of a schwannoma cell line from a patient with neurofibromatosis 2. Int J Oncol. 2002;20:475–82.

    CAS  PubMed  Google Scholar 

  15. Lepont P, Stickney JT, Foster LA, Meng JJ, Hennigan RF, Ip W. Point mutation in the NF2 gene of HEI-193 human schwannoma cells results in the expression of a merlin isoform with attenuated growth suppressive activity. Mutat Res. 2008;637:142–51.

    Article  CAS  Google Scholar 

  16. Tanaka K, Eskin A, Chareyre F, Jessen WJ, Manent J, Niwa-Kawakita M, et al. Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2. Clin Cancer Res. 2013;19:3856–70.

    Article  CAS  Google Scholar 

  17. Wray S, Self M, Consortium NPsDi, Consortium NPsDi, Consortium NAi, Lewis PA, et al. Creation of an open-access, mutation-defined fibroblast resource for neurological disease research. PLoS ONE 2012;7:e43099.

    Article  CAS  Google Scholar 

  18. Brown AM, Lemke G. Multiple regulatory elements control transcription of the peripheral myelin protein zero gene. J Biol Chem. 1997;272:28939–47.

    Article  CAS  Google Scholar 

  19. McCarty DM, Fu H, Monahan PE, Toulson CE, Naik P, Samulski RJ. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 2003;10:2112–8.

    Article  CAS  Google Scholar 

  20. Broekman ML, Comer LA, Hyman BT, Sena-Esteves M. Adeno-associated virus vectors serotyped with AAV8 capsid are more efficient than AAV-1 or -2 serotypes for widespread gene delivery to the neonatal mouse brain. Neuroscience. 2006;138:501–10.

    Article  CAS  Google Scholar 

  21. Saydam O, Ozdener GB, Senol O, Mizrak A, Prabhakar S, Stemmer-Rachamimov AO, et al. A novel imaging-compatible sciatic nerve schwannoma model. J Neurosci Methods. 2011;195:75–7.

    Article  Google Scholar 

  22. Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci. 2007;10:870–9.

    Article  CAS  Google Scholar 

  23. Kirschbaum KM, Hiemke C, Schmitt U. Rotarod impairment: catalepsy-like screening test for antipsychotic side effects. Int J Neurosci. 2009;119:1509–22.

    Article  CAS  Google Scholar 

  24. Chen Q, Peto CA, Shelton GD, Mizisin A, Sawchenko PE, Schubert D. Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration. J Neurosci. 2009;29:118–30.

    Article  Google Scholar 

  25. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:77–88.

    Article  CAS  Google Scholar 

  26. Messerli SM, Tang Y, Giovannini M, Bronson R, Weissleder R, Breakefield XO. Detection of spontaneous schwannomas by MRI in a transgenic murine model of neurofibromatosis type 2. Neoplasia. 2002;4:501–9.

    Article  CAS  Google Scholar 

  27. Harris JE, Sheean PM, Gleason PM, Bruemmer B, Boushey C. Publishing nutrition research: a review of multivariate techniques--part 2: analysis of variance. J Acad Nutr Diet. 2012;112:90–8.

    Article  Google Scholar 

  28. Sborgi L, Ruhl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, et al. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 2016;35:1766–78.

    Article  CAS  Google Scholar 

  29. Prabhakar S, Messerli SM, Stemmer-Rachamimov AO, Liu TC, Rabkin S, Martuza R, et al. Treatment of implantable NF2 schwannoma tumor models with oncolytic herpes simplex virus G47Delta. Cancer Gene Ther. 2007;14:460–7.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Marco Giovannini, M.D., Ph.D. (UCLA Health) for the HEI-193 and 08031-9 cell lines, and Timothy Houle, Ph.D. (Department of Anesthesia, Critical Care and Pain Medicine, MGH) for his assistance with statistical analysis.

Funding

This work was supported by NIH/NINDS R01 NS081146, NIH/NINDS tR21 NS088013, and a charitable donation from Neurofibromatosis Northeast to the Rebecca Grasso Fund.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Sherif G. Ahmed, Ahmed Abdelanabi, Mohamed Doha & Gary J. Brenner

Authors
  1. Sherif G. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmed Abdelanabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed Doha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gary J. Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary J. Brenner.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ahmed, S.G., Abdelanabi, A., Doha, M. et al. Schwannoma gene therapy by adeno-associated virus delivery of the pore-forming protein Gasdermin-D. Cancer Gene Ther 26, 259–267 (2019). https://doi.org/10.1038/s41417-018-0077-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-018-0077-3

This article is cited by

Search

Advanced search

Quick links