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Open Access 17-05-2024 | Gene Therapy in Oncology | Review

Gene Therapy for Neurofibromatosis Type 2-Related Schwannomatosis: Recent Progress, Challenges, and Future Directions

Authors: Ruofei Yuan, Bo Wang, Ying Wang, Pinan Liu

Published in: Oncology and Therapy | Issue 2/2024

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Abstract

Neurofibromatosis type 2 (NF2)-related schwannomatosis is a rare autosomal dominant monogenic disorder caused by mutations in the NF2 gene. The hallmarks of NF2-related schwannomatosis are bilateral vestibular schwannomas (VS). The current treatment options for NF2-related schwannomatosis, such as observation with serial imaging, surgery, radiotherapy, and pharmacotherapies, have shown limited effectiveness and serious complications. Therefore, there is a critical demand for novel effective treatments. Gene therapy, which has made significant advancements in treating genetic diseases, holds promise for the treatment of this disease. This review covers the genetic pathogenesis of NF2-related schwannomatosis, the latest progress in gene therapy strategies, current challenges, and future directions of gene therapy for NF2-related schwannomatosis.
Literature
1.
go back to reference Evans DG, Huson SM, Donnai D, et al. A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet. 1992;29:841–6.CrossRefPubMedPubMedCentral Evans DG, Huson SM, Donnai D, et al. A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet. 1992;29:841–6.CrossRefPubMedPubMedCentral
2.
go back to reference Evans DG, Moran A, King A, et al. Incidence of vestibular schwannoma and neurofibromatosis 2 in the Northwest of England over a 10-year period: higher incidence than previously thought. Otol Neurotol. 2005;26:93–7.CrossRefPubMed Evans DG, Moran A, King A, et al. Incidence of vestibular schwannoma and neurofibromatosis 2 in the Northwest of England over a 10-year period: higher incidence than previously thought. Otol Neurotol. 2005;26:93–7.CrossRefPubMed
3.
go back to reference Baser ME, Kuramoto L, Joe H, et al. Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. Am J Hum Genet. 2004;75:231–9.CrossRefPubMedPubMedCentral Baser ME, Kuramoto L, Joe H, et al. Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. Am J Hum Genet. 2004;75:231–9.CrossRefPubMedPubMedCentral
4.
go back to reference Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152a:327–32.CrossRefPubMed Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152a:327–32.CrossRefPubMed
5.
go back to reference Evans DG, Ramsden RT, Shenton A, et al. Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet. 2007;44:424–8.CrossRefPubMedPubMedCentral Evans DG, Ramsden RT, Shenton A, et al. Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet. 2007;44:424–8.CrossRefPubMedPubMedCentral
6.
go back to reference Moyhuddin A, Baser ME, Watson C, et al. Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet. 2003;40:459–63.CrossRefPubMedPubMedCentral Moyhuddin A, Baser ME, Watson C, et al. Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J Med Genet. 2003;40:459–63.CrossRefPubMedPubMedCentral
7.
go back to reference Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Quart J Med. 1992;84:603–18.PubMed Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Quart J Med. 1992;84:603–18.PubMed
8.
go back to reference Parry DM, Eldridge R, Kaiser-Kupfer MI, et al. Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet. 1994;52:450–61.CrossRefPubMed Parry DM, Eldridge R, Kaiser-Kupfer MI, et al. Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet. 1994;52:450–61.CrossRefPubMed
9.
go back to reference MacCollin M, Mautner VF. The diagnosis and management of neurofibromatosis 2 in childhood. Semin Pediatr Neurol. 1998;5:243–52.CrossRefPubMed MacCollin M, Mautner VF. The diagnosis and management of neurofibromatosis 2 in childhood. Semin Pediatr Neurol. 1998;5:243–52.CrossRefPubMed
10.
go back to reference Mautner VF, Lindenau M, Baser ME, et al. Skin abnormalities in neurofibromatosis 2. Arch Dermatol. 1997;133:1539–43.CrossRefPubMed Mautner VF, Lindenau M, Baser ME, et al. Skin abnormalities in neurofibromatosis 2. Arch Dermatol. 1997;133:1539–43.CrossRefPubMed
11.
go back to reference Mautner VF, Lindenau M, Baser ME, et al. The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery. 1996;38:880–6.CrossRefPubMed Mautner VF, Lindenau M, Baser ME, et al. The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery. 1996;38:880–6.CrossRefPubMed
12.
go back to reference Bosch MM, Boltshauser E, Harpes P, Landau K. Ophthalmologic findings and long-term course in patients with neurofibromatosis type 2. Am J Ophthalmol. 2006;141:1068–77.CrossRefPubMed Bosch MM, Boltshauser E, Harpes P, Landau K. Ophthalmologic findings and long-term course in patients with neurofibromatosis type 2. Am J Ophthalmol. 2006;141:1068–77.CrossRefPubMed
13.
go back to reference Ragge NK, Baser ME, Riccardi VM, Falk RE. The ocular presentation of neurofibromatosis 2. Eye (Lond). 1997;11:12–8.CrossRefPubMed Ragge NK, Baser ME, Riccardi VM, Falk RE. The ocular presentation of neurofibromatosis 2. Eye (Lond). 1997;11:12–8.CrossRefPubMed
14.
go back to reference Ragge NK, Baser ME, Klein J, et al. Ocular abnormalities in neurofibromatosis 2. Am J Ophthalmol. 1995;120:634–41.CrossRefPubMed Ragge NK, Baser ME, Klein J, et al. Ocular abnormalities in neurofibromatosis 2. Am J Ophthalmol. 1995;120:634–41.CrossRefPubMed
16.
go back to reference Halliday D, Emmanouil B, Pretorius P, et al. Genetic Severity Score predicts clinical phenotype in NF2. J Med Genet. 2017;54:657–64.CrossRefPubMed Halliday D, Emmanouil B, Pretorius P, et al. Genetic Severity Score predicts clinical phenotype in NF2. J Med Genet. 2017;54:657–64.CrossRefPubMed
18.
go back to reference Evans DG. Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet Med. 2009;11:599–610.CrossRefPubMed Evans DG. Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet Med. 2009;11:599–610.CrossRefPubMed
19.
20.
go back to reference Mathieu D, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates. Neurosurgery. 2007;60:460–8.CrossRefPubMed Mathieu D, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, complications, and hearing preservation rates. Neurosurgery. 2007;60:460–8.CrossRefPubMed
21.
go back to reference Roche PH, Régis J, Pellet W, et al. Neurofibromatosis type 2. Preliminary results of gamma knife radiosurgery of vestibular schwannomas. Neurochirurgie. 2000;46:339–53.PubMed Roche PH, Régis J, Pellet W, et al. Neurofibromatosis type 2. Preliminary results of gamma knife radiosurgery of vestibular schwannomas. Neurochirurgie. 2000;46:339–53.PubMed
22.
go back to reference Kida Y, Kobayashi T, Tanaka T, Mori Y. Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surg Neurol. 2000;53:383–9.CrossRefPubMed Kida Y, Kobayashi T, Tanaka T, Mori Y. Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surg Neurol. 2000;53:383–9.CrossRefPubMed
23.
go back to reference Rowe JG, Radatz MW, Walton L, et al. Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry. 2003;74:1288–93.CrossRefPubMedPubMedCentral Rowe JG, Radatz MW, Walton L, et al. Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry. 2003;74:1288–93.CrossRefPubMedPubMedCentral
24.
go back to reference Dewan R, Pemov A, Kim HJ, et al. Evidence of polyclonality in neurofibromatosis type 2-associated multilobulated vestibular schwannomas. Neuro Oncol. 2015;17:566–73.CrossRefPubMed Dewan R, Pemov A, Kim HJ, et al. Evidence of polyclonality in neurofibromatosis type 2-associated multilobulated vestibular schwannomas. Neuro Oncol. 2015;17:566–73.CrossRefPubMed
26.
go back to reference Evans DG, Birch JM, Ramsden RT, et al. Malignant transformation and new primary tumors after therapeutic radiation for benign disease: substantial risks in certain tumor prone syndromes. J Med Genet. 2006;43:289–94.CrossRefPubMed Evans DG, Birch JM, Ramsden RT, et al. Malignant transformation and new primary tumors after therapeutic radiation for benign disease: substantial risks in certain tumor prone syndromes. J Med Genet. 2006;43:289–94.CrossRefPubMed
27.
go back to reference Balasubramaniam A, Shannon P, Hodaie M, et al. Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: case report and review of the literature. Neuro Oncol. 2007;9:447–53.CrossRefPubMedPubMedCentral Balasubramaniam A, Shannon P, Hodaie M, et al. Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: case report and review of the literature. Neuro Oncol. 2007;9:447–53.CrossRefPubMedPubMedCentral
28.
go back to reference Carlson ML, Babovic-Vuksanovic D, Messiaen L, et al. Radiation-induced rhabdomyosarcoma of the brainstem in a patient with neurofibromatosis type 2. J Neurosurg. 2010;112:81–7.CrossRefPubMed Carlson ML, Babovic-Vuksanovic D, Messiaen L, et al. Radiation-induced rhabdomyosarcoma of the brainstem in a patient with neurofibromatosis type 2. J Neurosurg. 2010;112:81–7.CrossRefPubMed
29.
go back to reference Plotkin SR, Stemmer-Rachamimov AO, Barker FG, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361:358–67.CrossRefPubMedPubMedCentral Plotkin SR, Stemmer-Rachamimov AO, Barker FG, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009;361:358–67.CrossRefPubMedPubMedCentral
30.
go back to reference Mautner VF, Nguyen R, Kutta H, et al. Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro Oncol. 2010;12:14–8.CrossRefPubMed Mautner VF, Nguyen R, Kutta H, et al. Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro Oncol. 2010;12:14–8.CrossRefPubMed
31.
go back to reference Plotkin SR, Merker VL, Halpin C, et al. Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients. Otol Neurotol. 2012;33:1046–52.CrossRefPubMed Plotkin SR, Merker VL, Halpin C, et al. Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients. Otol Neurotol. 2012;33:1046–52.CrossRefPubMed
32.
go back to reference Slusarz KM, Merker VL, Muzikansky A, et al. Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients. Cancer Chemother Pharmacol. 2014;73:1197–204.CrossRefPubMed Slusarz KM, Merker VL, Muzikansky A, et al. Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients. Cancer Chemother Pharmacol. 2014;73:1197–204.CrossRefPubMed
33.
go back to reference Karajannis MA, Legault G, Hagiwara M, et al. Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol. 2012;14:1163–70.CrossRefPubMedPubMedCentral Karajannis MA, Legault G, Hagiwara M, et al. Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol. 2012;14:1163–70.CrossRefPubMedPubMedCentral
34.
go back to reference Plotkin SR, Halpin C, McKenna MJ, et al. Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otol Neurotol. 2010;31:1135–43.CrossRefPubMedPubMedCentral Plotkin SR, Halpin C, McKenna MJ, et al. Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients. Otol Neurotol. 2010;31:1135–43.CrossRefPubMedPubMedCentral
35.
go back to reference Karajannis MA, Legault G, Fisher MJ, et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. 2014;16:1408–16.CrossRefPubMedPubMedCentral Karajannis MA, Legault G, Fisher MJ, et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. 2014;16:1408–16.CrossRefPubMedPubMedCentral
36.
go back to reference Goutagny S, Raymond E, Esposito-Farese M, et al. Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas. J Neurooncol. 2015;122:313–20.CrossRefPubMed Goutagny S, Raymond E, Esposito-Farese M, et al. Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas. J Neurooncol. 2015;122:313–20.CrossRefPubMed
37.
go back to reference Beauchamp RL, James MF, DeSouza PA, et al. A high-throughput kinome screen reveals serum/ glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas. Oncotarget. 2015;6(19):16981–97.CrossRefPubMedPubMedCentral Beauchamp RL, James MF, DeSouza PA, et al. A high-throughput kinome screen reveals serum/ glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas. Oncotarget. 2015;6(19):16981–97.CrossRefPubMedPubMedCentral
38.
go back to reference Karajannis MA, Legault G, Hagiwara M, et al. Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol. 2014;16(2):292–7.CrossRefPubMed Karajannis MA, Legault G, Hagiwara M, et al. Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol. 2014;16(2):292–7.CrossRefPubMed
39.
go back to reference Goutagny S, Marco G, Michel K. A 4-year phase II study of everolimus in NF2 patients with growing vestibular schwannomas. J Neurooncol. 2017;133:443–5.CrossRefPubMed Goutagny S, Marco G, Michel K. A 4-year phase II study of everolimus in NF2 patients with growing vestibular schwannomas. J Neurooncol. 2017;133:443–5.CrossRefPubMed
40.
go back to reference Ammoun S, Ristic N, Matthies C, et al. Targeting ERK1/2 activation and proliferation in human primary schwannoma cells with MEK1/2 inhibitor AZD6244. Neurobiol Dis. 2010;37(1):141–6.CrossRefPubMed Ammoun S, Ristic N, Matthies C, et al. Targeting ERK1/2 activation and proliferation in human primary schwannoma cells with MEK1/2 inhibitor AZD6244. Neurobiol Dis. 2010;37(1):141–6.CrossRefPubMed
41.
go back to reference Morrison H, Sperka T, Manent J, et al. Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Can Res. 2007;67(2):520–7.CrossRef Morrison H, Sperka T, Manent J, et al. Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Can Res. 2007;67(2):520–7.CrossRef
42.
go back to reference Bush ML, Oblinger J, Brendel V, et al. AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. Neuro Oncol. 2011;13(9):983–99.CrossRefPubMedPubMedCentral Bush ML, Oblinger J, Brendel V, et al. AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas. Neuro Oncol. 2011;13(9):983–99.CrossRefPubMedPubMedCentral
43.
go back to reference Lin TY, Fenger J, Murahari S, et al. AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated kit. Blood. 2010;115(21):4217–25.CrossRefPubMedPubMedCentral Lin TY, Fenger J, Murahari S, et al. AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated kit. Blood. 2010;115(21):4217–25.CrossRefPubMedPubMedCentral
44.
go back to reference Dilwali S, Briët MC, Kao SY, et al. Preclinical validation of anti-nuclear factor-kappa B therapy to inhibit human vestibular schwannoma growth. Mol Oncol. 2015;9:1359–70.CrossRefPubMedPubMedCentral Dilwali S, Briët MC, Kao SY, et al. Preclinical validation of anti-nuclear factor-kappa B therapy to inhibit human vestibular schwannoma growth. Mol Oncol. 2015;9:1359–70.CrossRefPubMedPubMedCentral
45.
go back to reference Dilwali S, Kao SY, Fujita T, et al. Nonsteroidal anti-inflammatory medications are cytostatic against human vestibular schwannomas. Transl Res. 2015;166:1–11.CrossRefPubMedPubMedCentral Dilwali S, Kao SY, Fujita T, et al. Nonsteroidal anti-inflammatory medications are cytostatic against human vestibular schwannomas. Transl Res. 2015;166:1–11.CrossRefPubMedPubMedCentral
46.
go back to reference Kandathil CK, Cunnane ME, McKenna MJ, et al. Correlation between aspirin intake and reduced growth of human vestibular schwannoma, volumetric analysis. Otol Neurotol. 2016;37:1428–34.CrossRefPubMed Kandathil CK, Cunnane ME, McKenna MJ, et al. Correlation between aspirin intake and reduced growth of human vestibular schwannoma, volumetric analysis. Otol Neurotol. 2016;37:1428–34.CrossRefPubMed
47.
go back to reference Van Gompel JJ, Agazzi S, Carlson ML, et al. Congress of neurological surgeons systematic review and evidence-based guidelines on emerging therapies for the treatment of patients with vestibular schwannomas. Neurosurgery. 2018;82:E52–4.CrossRefPubMed Van Gompel JJ, Agazzi S, Carlson ML, et al. Congress of neurological surgeons systematic review and evidence-based guidelines on emerging therapies for the treatment of patients with vestibular schwannomas. Neurosurgery. 2018;82:E52–4.CrossRefPubMed
48.
go back to reference Tamura R, Fujioka M, Morimoto Y, et al. A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2. Nat Commun. 2019;10:5758.CrossRefPubMedPubMedCentral Tamura R, Fujioka M, Morimoto Y, et al. A VEGF receptor vaccine demonstrates preliminary efficacy in neurofibromatosis type 2. Nat Commun. 2019;10:5758.CrossRefPubMedPubMedCentral
49.
go back to reference Tamura R, Morimoto Y, Sato M, et al. Difference in the hypoxic immunosuppressive microenvironment of patients with neurofibromatosis type 2 schwannomas and sporadic schwannomas. J Neurooncol. 2020;146:265–73.CrossRefPubMed Tamura R, Morimoto Y, Sato M, et al. Difference in the hypoxic immunosuppressive microenvironment of patients with neurofibromatosis type 2 schwannomas and sporadic schwannomas. J Neurooncol. 2020;146:265–73.CrossRefPubMed
50.
51.
go back to reference Williams DA, Thrasher AJ. Concise review, lessons learned from clinical trials of gene therapy in monogenic immunodeficiency diseases. Stem Cells Transl Med. 2014;3:636–42.CrossRefPubMedPubMedCentral Williams DA, Thrasher AJ. Concise review, lessons learned from clinical trials of gene therapy in monogenic immunodeficiency diseases. Stem Cells Transl Med. 2014;3:636–42.CrossRefPubMedPubMedCentral
52.
go back to reference High KA, Anguela XM. Adeno-associated viral vectors for the treatment of hemophilia. Hum Mol Genet. 2016;25:R36–41.CrossRefPubMed High KA, Anguela XM. Adeno-associated viral vectors for the treatment of hemophilia. Hum Mol Genet. 2016;25:R36–41.CrossRefPubMed
53.
go back to reference Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE), an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20:284–93.CrossRefPubMed Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE), an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20:284–93.CrossRefPubMed
54.
go back to reference Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current clinical applications of in vivo gene therapy with AAVs. Mol Ther. 2021;29:464–88.CrossRefPubMed Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current clinical applications of in vivo gene therapy with AAVs. Mol Ther. 2021;29:464–88.CrossRefPubMed
55.
go back to reference Rafii MS, Tuszynski MH, Thomas RG, et al. Adeno-associated viral vector (serotype 2)-nerve growth factor for patients with Alzheimer disease, a randomized clinical trial. JAMA Neurol. 2018;75:834–41.CrossRefPubMedPubMedCentral Rafii MS, Tuszynski MH, Thomas RG, et al. Adeno-associated viral vector (serotype 2)-nerve growth factor for patients with Alzheimer disease, a randomized clinical trial. JAMA Neurol. 2018;75:834–41.CrossRefPubMedPubMedCentral
56.
go back to reference Niethammer M, Tang CC, LeWitt PA, et al. Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease. JCI Insight. 2017;2:e90133.CrossRefPubMedPubMedCentral Niethammer M, Tang CC, LeWitt PA, et al. Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease. JCI Insight. 2017;2:e90133.CrossRefPubMedPubMedCentral
57.
go back to reference Janson C, McPhee S, Bilaniuk L, et al. Clinical protocol. Gene therapy of Canavan disease, AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther. 2002;13:1391–412.CrossRefPubMed Janson C, McPhee S, Bilaniuk L, et al. Clinical protocol. Gene therapy of Canavan disease, AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther. 2002;13:1391–412.CrossRefPubMed
58.
go back to reference Hwu WL, Muramatsu S, Tseng SH, et al. Gene therapy for aromatic l-amino acid decarboxylase deficiency. Sci Transl Med. 2012;4:134ra61.CrossRefPubMed Hwu WL, Muramatsu S, Tseng SH, et al. Gene therapy for aromatic l-amino acid decarboxylase deficiency. Sci Transl Med. 2012;4:134ra61.CrossRefPubMed
59.
go back to reference Bailey RM, Armao D, Nagabhushan Kalburgi S, Gray SJ. Development of intrathecal AAV9 gene therapy for giant axonal neuropathy. Mol Ther Methods Clin Dev. 2018;9:160–71.CrossRefPubMedPubMedCentral Bailey RM, Armao D, Nagabhushan Kalburgi S, Gray SJ. Development of intrathecal AAV9 gene therapy for giant axonal neuropathy. Mol Ther Methods Clin Dev. 2018;9:160–71.CrossRefPubMedPubMedCentral
60.
go back to reference Rouleau GA, Merel P, Lutchman M, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature. 1993;363:515–21.CrossRefPubMed Rouleau GA, Merel P, Lutchman M, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature. 1993;363:515–21.CrossRefPubMed
61.
go back to reference Trofatter JA, MacCollin MM, Rutter JL, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;72:791–800.CrossRefPubMed Trofatter JA, MacCollin MM, Rutter JL, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;72:791–800.CrossRefPubMed
62.
go back to reference Gusella JF, Ramesh V, MacCollin M, Jacoby LB. Merlin, the neurofibromatosis 2 tumor suppressor. Biochim Biophys Acta. 1999;1423:M29–36.PubMed Gusella JF, Ramesh V, MacCollin M, Jacoby LB. Merlin, the neurofibromatosis 2 tumor suppressor. Biochim Biophys Acta. 1999;1423:M29–36.PubMed
63.
go back to reference Shimizu T, Seto A, Maita N. Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain. J Biol Chem. 2002;277:10332–6.CrossRefPubMed Shimizu T, Seto A, Maita N. Structural basis for neurofibromatosis type 2. Crystal structure of the merlin FERM domain. J Biol Chem. 2002;277:10332–6.CrossRefPubMed
64.
go back to reference Scherer SS, Gutmann DH. Expression of the neurofibromatosis 2 tumor suppressor gene product, merlin, in Schwann cells. J Neurosci Res. 1996;46:595–605.CrossRefPubMed Scherer SS, Gutmann DH. Expression of the neurofibromatosis 2 tumor suppressor gene product, merlin, in Schwann cells. J Neurosci Res. 1996;46:595–605.CrossRefPubMed
65.
go back to reference Li W, Cooper J, Karajannis MA, Giancotti FG. Merlin, a tumour suppressor with functions at the cell cortex and in the nucleus. EMBO Rep. 2012;13:204–15.CrossRefPubMedPubMedCentral Li W, Cooper J, Karajannis MA, Giancotti FG. Merlin, a tumour suppressor with functions at the cell cortex and in the nucleus. EMBO Rep. 2012;13:204–15.CrossRefPubMedPubMedCentral
66.
go back to reference Bianchi AB, Hara T, Ramesh V, et al. Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumor types. Nat Genet. 1994;6:185–92.CrossRefPubMed Bianchi AB, Hara T, Ramesh V, et al. Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumor types. Nat Genet. 1994;6:185–92.CrossRefPubMed
67.
go back to reference Pykett MJ, Murphy M, Harnish PR, George DL. The neurofibromatosis 2(NF2) tumor suppressor gene encodes multiple alternatively spliced transcripts. Hum Mol Genet. 1994;3:559–64.CrossRefPubMed Pykett MJ, Murphy M, Harnish PR, George DL. The neurofibromatosis 2(NF2) tumor suppressor gene encodes multiple alternatively spliced transcripts. Hum Mol Genet. 1994;3:559–64.CrossRefPubMed
68.
go back to reference Sherman L, Xu HM, Geist RT, et al. Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene. 1997;15:2505–9.CrossRefPubMed Sherman L, Xu HM, Geist RT, et al. Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene. 1997;15:2505–9.CrossRefPubMed
69.
go back to reference Alfthan K, Heiska L, Gronholm M, et al. Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization. J Biol Chem. 2004;279:18559–66.CrossRefPubMed Alfthan K, Heiska L, Gronholm M, et al. Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization. J Biol Chem. 2004;279:18559–66.CrossRefPubMed
70.
go back to reference Kissil JL, Johnson KC, Eckman MS, Jacks T. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem. 2002;277:10394–9.CrossRefPubMed Kissil JL, Johnson KC, Eckman MS, Jacks T. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem. 2002;277:10394–9.CrossRefPubMed
71.
go back to reference Jin H, Sperka T, Herrlich P, Morrison H. Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase. Nature. 2006;442:576–9.CrossRefPubMed Jin H, Sperka T, Herrlich P, Morrison H. Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase. Nature. 2006;442:576–9.CrossRefPubMed
72.
go back to reference Rong R, Surace EI, Haipek CA, et al. Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression. Oncogene. 2004;23:8447–54.CrossRefPubMed Rong R, Surace EI, Haipek CA, et al. Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression. Oncogene. 2004;23:8447–54.CrossRefPubMed
73.
go back to reference Shaw RJ, Paez JG, Curto M, et al. The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell. 2001;1:63–72.CrossRefPubMed Shaw RJ, Paez JG, Curto M, et al. The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell. 2001;1:63–72.CrossRefPubMed
74.
go back to reference Asthagiri AR, Parry DM, Butman JA, et al. Neurofibromatosis type 2. Lancet. 2009;6(373):1974–86.CrossRef Asthagiri AR, Parry DM, Butman JA, et al. Neurofibromatosis type 2. Lancet. 2009;6(373):1974–86.CrossRef
75.
go back to reference Stamenkovic I, Yu Q. Merlin, a “magic” linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival. Curr Protein Pept Sci. 2010;11:471–84.CrossRefPubMedPubMedCentral Stamenkovic I, Yu Q. Merlin, a “magic” linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival. Curr Protein Pept Sci. 2010;11:471–84.CrossRefPubMedPubMedCentral
76.
go back to reference James MF, Han S, Polizzano C, et al. NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol. 2009;29:4250–61.CrossRefPubMedPubMedCentral James MF, Han S, Polizzano C, et al. NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol. 2009;29:4250–61.CrossRefPubMedPubMedCentral
77.
go back to reference López-Lago MA, Okada T, Murillo MM, et al. Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling. Mol Cell Biol. 2009;29:4235–49.CrossRefPubMedPubMedCentral López-Lago MA, Okada T, Murillo MM, et al. Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling. Mol Cell Biol. 2009;29:4235–49.CrossRefPubMedPubMedCentral
78.
go back to reference James MF, Stivison E, Beauchamp R, et al. Regulation of mTOR complex 2 signaling in neurofibromatosis 2-deficient target cell types. Mol Cancer Res. 2012;10:649–59.CrossRefPubMed James MF, Stivison E, Beauchamp R, et al. Regulation of mTOR complex 2 signaling in neurofibromatosis 2-deficient target cell types. Mol Cancer Res. 2012;10:649–59.CrossRefPubMed
79.
go back to reference McClatchey AI, Fehon RG. Merlin and the ERM proteins–regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol. 2009;19:198.CrossRefPubMedPubMedCentral McClatchey AI, Fehon RG. Merlin and the ERM proteins–regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol. 2009;19:198.CrossRefPubMedPubMedCentral
80.
go back to reference Yi C, Wilker EW, Yaffe MB, et al. Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2. Cancer Res. 2008;68:7932–7.CrossRefPubMedPubMedCentral Yi C, Wilker EW, Yaffe MB, et al. Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2. Cancer Res. 2008;68:7932–7.CrossRefPubMedPubMedCentral
81.
go back to reference Hamaratoglu F, Willecke M, Kango-Singh M, et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2006;8:27–36.CrossRefPubMed Hamaratoglu F, Willecke M, Kango-Singh M, et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2006;8:27–36.CrossRefPubMed
82.
go back to reference Yin F, Yu J, Zheng Y, et al. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell. 2013;154:1342–55.CrossRefPubMed Yin F, Yu J, Zheng Y, et al. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell. 2013;154:1342–55.CrossRefPubMed
83.
go back to reference Li W, You L, Cooper J, et al. Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. Cell. 2010;140:477–90.CrossRefPubMedPubMedCentral Li W, You L, Cooper J, et al. Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. Cell. 2010;140:477–90.CrossRefPubMedPubMedCentral
84.
go back to reference Ammoun S, Hanemann CO. Emerging therapeutic targets in schwannomas and other merlin-deficient tumors. Nat Rev Neurol. 2011;7:392–9.CrossRefPubMed Ammoun S, Hanemann CO. Emerging therapeutic targets in schwannomas and other merlin-deficient tumors. Nat Rev Neurol. 2011;7:392–9.CrossRefPubMed
85.
go back to reference McClatchey AI, Giovannini M. Membrane organization and tumorigenesis–the NF2 tumor suppressor, merlin. Genes Dev. 2005;19:2265–77.CrossRefPubMed McClatchey AI, Giovannini M. Membrane organization and tumorigenesis–the NF2 tumor suppressor, merlin. Genes Dev. 2005;19:2265–77.CrossRefPubMed
86.
go back to reference Scoles DR. The merlin interacting proteins reveal multiple targets for NF2 therapy. Biochim Biophys Acta. 2008;1785:32–54.PubMed Scoles DR. The merlin interacting proteins reveal multiple targets for NF2 therapy. Biochim Biophys Acta. 2008;1785:32–54.PubMed
87.
go back to reference Hartmann M, Parra LM, Ruschel A, et al. Tumor suppressor NF2 blocks cellular migration by inhibiting ectodomain cleavage of CD44. Mol Cancer Res. 2015;13:879–90.CrossRefPubMed Hartmann M, Parra LM, Ruschel A, et al. Tumor suppressor NF2 blocks cellular migration by inhibiting ectodomain cleavage of CD44. Mol Cancer Res. 2015;13:879–90.CrossRefPubMed
88.
go back to reference Fernandez-Valle C, Tang Y, Ricard J, et al. Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology. Nat Genet. 2002;31:354–62.CrossRefPubMed Fernandez-Valle C, Tang Y, Ricard J, et al. Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology. Nat Genet. 2002;31:354–62.CrossRefPubMed
89.
go back to reference James MF, Manchanda N, Gonzalez-Agosti C, et al. The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association. Biochem J. 2001;356:377–86.CrossRefPubMedPubMedCentral James MF, Manchanda N, Gonzalez-Agosti C, et al. The neurofibromatosis 2 protein product merlin selectively binds F-actin but not G-actin, and stabilizes the filaments through a lateral association. Biochem J. 2001;356:377–86.CrossRefPubMedPubMedCentral
90.
go back to reference Wiederhold T, Lee MF, James M, et al. Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2. Oncogene. 2004;23:8815–25.CrossRefPubMed Wiederhold T, Lee MF, James M, et al. Magicin, a novel cytoskeletal protein associates with the NF2 tumor suppressor merlin and Grb2. Oncogene. 2004;23:8815–25.CrossRefPubMed
92.
go back to reference Morrison H, Sherman L, Legg J, et al. The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev. 2001;15:968–80.CrossRefPubMedPubMedCentral Morrison H, Sherman L, Legg J, et al. The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev. 2001;15:968–80.CrossRefPubMedPubMedCentral
93.
go back to reference Okada T, Lopez-Lago M, Giancotti FG. Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane. J Cell Biol. 2005;171:361–71.CrossRefPubMedPubMedCentral Okada T, Lopez-Lago M, Giancotti FG. Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane. J Cell Biol. 2005;171:361–71.CrossRefPubMedPubMedCentral
94.
go back to reference Lallemand D, Curto M, Saotome I, et al. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. 2003;17:1090–100.CrossRefPubMedPubMedCentral Lallemand D, Curto M, Saotome I, et al. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. 2003;17:1090–100.CrossRefPubMedPubMedCentral
96.
97.
go back to reference Kluwe L, Mautner V, Heinrich B, et al. Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet. 2003;40:109–14.CrossRefPubMedPubMedCentral Kluwe L, Mautner V, Heinrich B, et al. Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet. 2003;40:109–14.CrossRefPubMedPubMedCentral
98.
go back to reference Evans DG, Hartley CL, Smith PT, et al. Incidence of mosaicism in 1055 de novo NF2 cases, much higher than previous estimates with high utility of next-generation sequencing. Genet Med. 2020;22(1):53–9.CrossRefPubMed Evans DG, Hartley CL, Smith PT, et al. Incidence of mosaicism in 1055 de novo NF2 cases, much higher than previous estimates with high utility of next-generation sequencing. Genet Med. 2020;22(1):53–9.CrossRefPubMed
99.
go back to reference Teranishi Y, Miyawaki S, Hongo H, et al. Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2. J Med Genet. 2021;58:701–11.CrossRefPubMed Teranishi Y, Miyawaki S, Hongo H, et al. Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2. J Med Genet. 2021;58:701–11.CrossRefPubMed
100.
go back to reference Evans DG, Ramsden RT, Shenton A, et al. What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors? J Neurosurg. 2008;108:92–6.CrossRefPubMed Evans DG, Ramsden RT, Shenton A, et al. What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors? J Neurosurg. 2008;108:92–6.CrossRefPubMed
101.
go back to reference Ahronowitz I, Xin W, Kiely R, Sims K, et al. Mutational spectrum of the NF2 gene, a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat. 2007;28:1–12.CrossRefPubMed Ahronowitz I, Xin W, Kiely R, Sims K, et al. Mutational spectrum of the NF2 gene, a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat. 2007;28:1–12.CrossRefPubMed
102.
go back to reference Hadfield KD, Smith MJ, Urquhart JE, et al. Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas. Oncogene. 2010;29:6216–21.CrossRefPubMed Hadfield KD, Smith MJ, Urquhart JE, et al. Rates of loss of heterozygosity and mitotic recombination in NF2 schwannomas, sporadic vestibular schwannomas and schwannomatosis schwannomas. Oncogene. 2010;29:6216–21.CrossRefPubMed
103.
go back to reference Petrilli AM, Fernandez-Valle C. Role of Merlin/NF2 inactivation in tumor biology. Oncogene. 2016;35:537–48.CrossRefPubMed Petrilli AM, Fernandez-Valle C. Role of Merlin/NF2 inactivation in tumor biology. Oncogene. 2016;35:537–48.CrossRefPubMed
104.
go back to reference Parry DM, MacCollin MM, Kaiser-Kupfer MI, et al. Germ-line mutations in the neurofibromatosis 2 gene, correlations with disease severity and retinal abnormalities. Am J Hum Genet. 1996;59:529–39.PubMedPubMedCentral Parry DM, MacCollin MM, Kaiser-Kupfer MI, et al. Germ-line mutations in the neurofibromatosis 2 gene, correlations with disease severity and retinal abnormalities. Am J Hum Genet. 1996;59:529–39.PubMedPubMedCentral
105.
go back to reference Evans DG, Trueman L, Wallace A, Collins S, et al. Genotype/phenotype correlations in type 2 neurofibromatosis (NF2), evidence for more severe disease associated with truncating mutations. J Med Genet. 1998;35:450–5.CrossRefPubMedPubMedCentral Evans DG, Trueman L, Wallace A, Collins S, et al. Genotype/phenotype correlations in type 2 neurofibromatosis (NF2), evidence for more severe disease associated with truncating mutations. J Med Genet. 1998;35:450–5.CrossRefPubMedPubMedCentral
106.
go back to reference Baser ME, Kuramoto L, Woods R, et al. The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet. 2005;42:540–6.CrossRefPubMedPubMedCentral Baser ME, Kuramoto L, Woods R, et al. The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet. 2005;42:540–6.CrossRefPubMedPubMedCentral
107.
go back to reference Dow G, Biggs N, Evans G, et al. Spinal tumors in neurofibromatosis type 2. Is emerging knowledge of genotype predictive of natural history? J Neurosurg Spine. 2005;2:574–9.CrossRefPubMed Dow G, Biggs N, Evans G, et al. Spinal tumors in neurofibromatosis type 2. Is emerging knowledge of genotype predictive of natural history? J Neurosurg Spine. 2005;2:574–9.CrossRefPubMed
108.
go back to reference Baser ME, Makariou EV, Parry DM. Predictors of vestibular schwannoma growth in patients with neurofibromatosis type 2. J Neurosurg. 2002;96:217–22.CrossRefPubMed Baser ME, Makariou EV, Parry DM. Predictors of vestibular schwannoma growth in patients with neurofibromatosis type 2. J Neurosurg. 2002;96:217–22.CrossRefPubMed
109.
110.
go back to reference Baser ME, Kluwe L, Mautner VF. Germline NF2 mutations and disease severity in neurofibromatosis type 2 patients with retinal abnormalities. Am J Hum Genet. 1999;64:1230–3.CrossRefPubMedPubMedCentral Baser ME, Kluwe L, Mautner VF. Germline NF2 mutations and disease severity in neurofibromatosis type 2 patients with retinal abnormalities. Am J Hum Genet. 1999;64:1230–3.CrossRefPubMedPubMedCentral
111.
go back to reference Verma A, Jaiswal P. Neurofibromatosis type-2, a pathological mechanism. World J Pharm Res. 2022;11(9):1536–51. Verma A, Jaiswal P. Neurofibromatosis type-2, a pathological mechanism. World J Pharm Res. 2022;11(9):1536–51.
112.
113.
go back to reference Prabhakar S, Brennan GJ, Messerli SM, 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.CrossRefPubMed Prabhakar S, Brennan GJ, Messerli SM, 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.CrossRefPubMed
114.
go back to reference Prabhakar S, Taherian M, Gianni D, et al. Regression of schwannomas induced by adeno-associated virus-mediated delivery of caspase-1. Hum Gene Ther. 2013;24(2):152–62.CrossRefPubMed Prabhakar S, Taherian M, Gianni D, et al. Regression of schwannomas induced by adeno-associated virus-mediated delivery of caspase-1. Hum Gene Ther. 2013;24(2):152–62.CrossRefPubMed
115.
go back to reference Ahmed SG, Abdelanabi A, Doha M, Brenner GJ. Schwannoma gene therapy by adeno-associated virus delivery of the pore-forming protein Gasdermin-D. Cancer Gene Ther. 2019;26:259–67.CrossRefPubMed Ahmed SG, Abdelanabi A, Doha M, Brenner GJ. Schwannoma gene therapy by adeno-associated virus delivery of the pore-forming protein Gasdermin-D. Cancer Gene Ther. 2019;26:259–67.CrossRefPubMed
116.
go back to reference Ahmed SG, Abdelnabi A, Maguire CA, et al. Gene therapy with apoptosis-associated speck-like protein, a newly described schwannoma tumor suppressor, inhibits schwannoma growth in vivo. Neuro Oncol. 2019;21:854–66.CrossRefPubMedPubMedCentral Ahmed SG, Abdelnabi A, Maguire CA, et al. Gene therapy with apoptosis-associated speck-like protein, a newly described schwannoma tumor suppressor, inhibits schwannoma growth in vivo. Neuro Oncol. 2019;21:854–66.CrossRefPubMedPubMedCentral
117.
go back to reference Prabhakar S, Beauchamp RL, Cheah PS, et al. Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2. Mol Ther Methods Clin Dev. 2022;26:169–80.CrossRefPubMedPubMedCentral Prabhakar S, Beauchamp RL, Cheah PS, et al. Gene replacement therapy in a schwannoma mouse model of neurofibromatosis type 2. Mol Ther Methods Clin Dev. 2022;26:169–80.CrossRefPubMedPubMedCentral
119.
go back to reference Hall J, Prabhakar S, Balaj L, et al. Delivery of therapeutic proteins via extracellular vesicles, review and potential treatments for Parkinson’s disease, glioma and schwannoma. Cell Mol Neurobiol. 2016;36:417–27.CrossRefPubMedPubMedCentral Hall J, Prabhakar S, Balaj L, et al. Delivery of therapeutic proteins via extracellular vesicles, review and potential treatments for Parkinson’s disease, glioma and schwannoma. Cell Mol Neurobiol. 2016;36:417–27.CrossRefPubMedPubMedCentral
120.
go back to reference Mizrak A, Bolukbasi MF, Ozdener GB, et al. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther. 2013;21:101–8.CrossRefPubMed Mizrak A, Bolukbasi MF, Ozdener GB, et al. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther. 2013;21:101–8.CrossRefPubMed
121.
go back to reference Keiser MS, Kordasiewicz HB, McBride JL. Gene suppression strategies for dominantly inherited neurodegenerative diseases, lessons from Huntington’s disease and spinocerebellar ataxia. Hum Mol Genet. 2016;25:R53–64.CrossRefPubMed Keiser MS, Kordasiewicz HB, McBride JL. Gene suppression strategies for dominantly inherited neurodegenerative diseases, lessons from Huntington’s disease and spinocerebellar ataxia. Hum Mol Genet. 2016;25:R53–64.CrossRefPubMed
122.
go back to reference Garrelfs SF, Frishberg Y, Hulton SA, et al. An RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med. 2021;384(13):1216–26.CrossRefPubMed Garrelfs SF, Frishberg Y, Hulton SA, et al. An RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med. 2021;384(13):1216–26.CrossRefPubMed
123.
go back to reference Strumberg D, Schultheis B, Traugott U, et al. Phase I clinical development of Atu027, a siRNA formulation targeting PKN3 in patients with advanced solid tumors. Int J Clin Pharmacol Ther. 2012;50(1):76–8.CrossRefPubMed Strumberg D, Schultheis B, Traugott U, et al. Phase I clinical development of Atu027, a siRNA formulation targeting PKN3 in patients with advanced solid tumors. Int J Clin Pharmacol Ther. 2012;50(1):76–8.CrossRefPubMed
124.
go back to reference Carson AR, McTiernan CF, Lavery L, et al. Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy. Cancer Res. 2012;72(23):6191–9.CrossRefPubMedPubMedCentral Carson AR, McTiernan CF, Lavery L, et al. Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy. Cancer Res. 2012;72(23):6191–9.CrossRefPubMedPubMedCentral
125.
go back to reference Kesharwani P, Gajbhiye V, Jain NK. A review of nanocarriers for the delivery of small interfering RNA. Biomaterials. 2012;33(29):7138–50.CrossRefPubMed Kesharwani P, Gajbhiye V, Jain NK. A review of nanocarriers for the delivery of small interfering RNA. Biomaterials. 2012;33(29):7138–50.CrossRefPubMed
126.
go back to reference Santel A, Aleku M, Roder N, et al. Atu027 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models. Clin Cancer Res. 2010;16(22):5469–80.CrossRefPubMed Santel A, Aleku M, Roder N, et al. Atu027 prevents pulmonary metastasis in experimental and spontaneous mouse metastasis models. Clin Cancer Res. 2010;16(22):5469–80.CrossRefPubMed
127.
go back to reference Ponder KP. Vectors in gene therapy. In: Kresnia TF, editor. An introduction to molecular medicine and gene therapy. New York: Wiley; 2000. p. 77–112.CrossRef Ponder KP. Vectors in gene therapy. In: Kresnia TF, editor. An introduction to molecular medicine and gene therapy. New York: Wiley; 2000. p. 77–112.CrossRef
128.
130.
132.
go back to reference Gao G, Vandenberghe LH, Wilson JM. New recombinant serotypes of AAV vectors. Curr Gene Ther. 2005;5:285–97.CrossRefPubMed Gao G, Vandenberghe LH, Wilson JM. New recombinant serotypes of AAV vectors. Curr Gene Ther. 2005;5:285–97.CrossRefPubMed
133.
go back to reference Pipe S, Leebeek FWG, Ferreira V, et al. Clinical considerations for capsid choice in the development of liver-targeted AAV-based gene transfer. Mol Ther Methods Clin Dev. 2019;15:170–8.CrossRefPubMedPubMedCentral Pipe S, Leebeek FWG, Ferreira V, et al. Clinical considerations for capsid choice in the development of liver-targeted AAV-based gene transfer. Mol Ther Methods Clin Dev. 2019;15:170–8.CrossRefPubMedPubMedCentral
135.
136.
go back to reference Pietersz KL, Martier RM, Baatje MS, et al. Transduction patterns in the CNS following various routes of AVV-5-mediated gene delivery. Gene Ther. 2021;28:435–46.CrossRefPubMed Pietersz KL, Martier RM, Baatje MS, et al. Transduction patterns in the CNS following various routes of AVV-5-mediated gene delivery. Gene Ther. 2021;28:435–46.CrossRefPubMed
138.
go back to reference Akil O, Dyka F, Calvet C, et al. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proc Natl Acad Sci USA. 2019;116(10):4496–501.CrossRefPubMedPubMedCentral Akil O, Dyka F, Calvet C, et al. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proc Natl Acad Sci USA. 2019;116(10):4496–501.CrossRefPubMedPubMedCentral
139.
go back to reference Zuris JA, Thompson DB, Shu Y, et al. Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol. 2015;33(1):73–80.CrossRefPubMed Zuris JA, Thompson DB, Shu Y, et al. Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol. 2015;33(1):73–80.CrossRefPubMed
142.
go back to reference Ren Y, Chari DA, Vasilijic S, et al. New developments in neurofibromatosis type 2 and vestibular schwannoma. Neuro-Oncol Adv. 2021;3(1):1–13. Ren Y, Chari DA, Vasilijic S, et al. New developments in neurofibromatosis type 2 and vestibular schwannoma. Neuro-Oncol Adv. 2021;3(1):1–13.
144.
go back to reference Penaud-Budloo M, François A, Clément N, Ayuso E. Pharmacology of recombinant adeno-associated virus production. Mol Ther Methods Clin Dev. 2018;8:166–80.CrossRefPubMedPubMedCentral Penaud-Budloo M, François A, Clément N, Ayuso E. Pharmacology of recombinant adeno-associated virus production. Mol Ther Methods Clin Dev. 2018;8:166–80.CrossRefPubMedPubMedCentral
145.
go back to reference Tang Q, Keeler AM, Zhang S, et al. Two-plasmid packaging system for recombinant adeno-associated virus. Biores. 2020;9:219–28. Tang Q, Keeler AM, Zhang S, et al. Two-plasmid packaging system for recombinant adeno-associated virus. Biores. 2020;9:219–28.
146.
go back to reference Robert MA, Chahal PS, Audy A, et al. Manufacturing of recombinant adeno-associated viruses using mammalian expression platforms. Biotechnol J. 2017;12:1600193–216.CrossRef Robert MA, Chahal PS, Audy A, et al. Manufacturing of recombinant adeno-associated viruses using mammalian expression platforms. Biotechnol J. 2017;12:1600193–216.CrossRef
147.
go back to reference Moleirinho MG, Silva RJS, Alves PM, et al. Current challenges in biotherapeutic particles manufacturing. Expert Opin Biol Ther. 2020;20:451–65.CrossRefPubMed Moleirinho MG, Silva RJS, Alves PM, et al. Current challenges in biotherapeutic particles manufacturing. Expert Opin Biol Ther. 2020;20:451–65.CrossRefPubMed
148.
go back to reference Grieger JC, Soltys SM, Samulski RJ. Production of recombinant adeno- associated virus vectors using suspension HEK293 cells and continuous harvest of vector from the culture media for GMP FIX and FLT1 clinical vector. Mol Ther. 2016;24:287–97.CrossRefPubMed Grieger JC, Soltys SM, Samulski RJ. Production of recombinant adeno- associated virus vectors using suspension HEK293 cells and continuous harvest of vector from the culture media for GMP FIX and FLT1 clinical vector. Mol Ther. 2016;24:287–97.CrossRefPubMed
149.
go back to reference Hung G, Li X, Faudoa R, et al. Establishment and characterization of a schwannoma cell line from a patient with neurofibromatosis 2. Int J Oncol. 2002;20(3):475–82.PubMed Hung G, Li X, Faudoa R, et al. Establishment and characterization of a schwannoma cell line from a patient with neurofibromatosis 2. Int J Oncol. 2002;20(3):475–82.PubMed
150.
go back to reference Zhao F, Chen Y, Li SW, et al. Novel patient derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma. J Pathol. 2022;257(5):620–34.CrossRefPubMed Zhao F, Chen Y, Li SW, et al. Novel patient derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma. J Pathol. 2022;257(5):620–34.CrossRefPubMed
151.
go back to reference Saydam O, Ozdener GB, Senol O, et al. A novel imaging-compatible sciatic nerve schwannoma model. J Neurosci Methods. 2011;195(1):75–7.CrossRefPubMed Saydam O, Ozdener GB, Senol O, et al. A novel imaging-compatible sciatic nerve schwannoma model. J Neurosci Methods. 2011;195(1):75–7.CrossRefPubMed
152.
go back to reference Gao X, Zhao Y, Stemmer-Rachamimov AO, et al. Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model. Proc Natl Acad Sci USA. 2015;112(47):14676–81.CrossRefPubMedPubMedCentral Gao X, Zhao Y, Stemmer-Rachamimov AO, et al. Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model. Proc Natl Acad Sci USA. 2015;112(47):14676–81.CrossRefPubMedPubMedCentral
153.
go back to reference Bonne NX, Vitte J, Chareyre F, et al. An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth. Neuro Oncol. 2016;129:47–56.CrossRef Bonne NX, Vitte J, Chareyre F, et al. An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth. Neuro Oncol. 2016;129:47–56.CrossRef
154.
go back to reference Gehlhausen JR, Park SJ, Hickox AE, et al. A murine model of neurofibromatosis type2that accurately phenocopies human schwannoma formation. Hum Mol Genet. 2015;24:1–8.CrossRefPubMed Gehlhausen JR, Park SJ, Hickox AE, et al. A murine model of neurofibromatosis type2that accurately phenocopies human schwannoma formation. Hum Mol Genet. 2015;24:1–8.CrossRefPubMed
155.
go back to reference Chen J, Landegger LD, Sun Y, et al. A cerebellopontine angle mouse model for the investigation of tumor biology, hearing, and neurological function in NF2-related vestibular schwannoma. Nat Protoc. 2019;14:541–55.CrossRefPubMedPubMedCentral Chen J, Landegger LD, Sun Y, et al. A cerebellopontine angle mouse model for the investigation of tumor biology, hearing, and neurological function in NF2-related vestibular schwannoma. Nat Protoc. 2019;14:541–55.CrossRefPubMedPubMedCentral
156.
go back to reference Giovannini M, Robanus-Maandag E, van der Valk M, et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 2000;14:1617–30.CrossRefPubMedPubMedCentral Giovannini M, Robanus-Maandag E, van der Valk M, et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 2000;14:1617–30.CrossRefPubMedPubMedCentral
157.
go back to reference Charabi S, Rygaard J, Klinken L, et al. Subcutaneous growth of human acoustic schwannomas in athymic nude mice. Acta Otolaryngol. 1994;114:399–405.CrossRefPubMed Charabi S, Rygaard J, Klinken L, et al. Subcutaneous growth of human acoustic schwannomas in athymic nude mice. Acta Otolaryngol. 1994;114:399–405.CrossRefPubMed
158.
go back to reference Stidham KR, Roberson JB Jr. Human vestibular schwannoma growth in the nude mouse: evaluation of a modified subcutaneous implantation model. Am J Otol. 1997;18:622–6.PubMed Stidham KR, Roberson JB Jr. Human vestibular schwannoma growth in the nude mouse: evaluation of a modified subcutaneous implantation model. Am J Otol. 1997;18:622–6.PubMed
159.
162.
go back to reference Zhang F, Wen Y, Guo X. CRISPR/Cas9 for genome editing, progress, implications and challenges. Hum Mol Genet. 2014;23:R40–6.CrossRefPubMed Zhang F, Wen Y, Guo X. CRISPR/Cas9 for genome editing, progress, implications and challenges. Hum Mol Genet. 2014;23:R40–6.CrossRefPubMed
163.
168.
go back to reference Maeder ML, Stefanidakis M, Wilson CJ, et al. Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nat Med. 2019;25:229–33.CrossRefPubMed Maeder ML, Stefanidakis M, Wilson CJ, et al. Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nat Med. 2019;25:229–33.CrossRefPubMed
169.
go back to reference Shahryari A, Saghaeian Jazi M, Mohammadi S, et al. Development and clinical translation of approved gene therapy products for genetic disorders. Front Genet. 2019;10:868.CrossRefPubMedPubMedCentral Shahryari A, Saghaeian Jazi M, Mohammadi S, et al. Development and clinical translation of approved gene therapy products for genetic disorders. Front Genet. 2019;10:868.CrossRefPubMedPubMedCentral
171.
172.
go back to reference Foldvari M, Chen DW, Nafissi N, et al. Non-viral gene therapy, gains and challenges of noninvasive administration methods. J Control Release. 2016;240:165–90.CrossRefPubMed Foldvari M, Chen DW, Nafissi N, et al. Non-viral gene therapy, gains and challenges of noninvasive administration methods. J Control Release. 2016;240:165–90.CrossRefPubMed
174.
go back to reference Fukuda M, Oishi M, Hiraishi T, et al. Clinicopathological factors related to regrowth of vestibular schwannoma after incomplete resection. J Neurosurg. 2011;114(5):1224–31.CrossRefPubMed Fukuda M, Oishi M, Hiraishi T, et al. Clinicopathological factors related to regrowth of vestibular schwannoma after incomplete resection. J Neurosurg. 2011;114(5):1224–31.CrossRefPubMed
175.
go back to reference Lewis D, Roncaroli F, Agushi E, et al. Inflammation and vascular permeability correlate with growth in sporadic vestibular schwannoma. Neuro Oncol. 2019;21(3):314–25.CrossRefPubMed Lewis D, Roncaroli F, Agushi E, et al. Inflammation and vascular permeability correlate with growth in sporadic vestibular schwannoma. Neuro Oncol. 2019;21(3):314–25.CrossRefPubMed
176.
go back to reference Wong HK, Lahdenranta J, Kamoun WS, et al. Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors. Cancer Res. 2010;70(9):3483–93.CrossRefPubMedPubMedCentral Wong HK, Lahdenranta J, Kamoun WS, et al. Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors. Cancer Res. 2010;70(9):3483–93.CrossRefPubMedPubMedCentral
177.
go back to reference Blakeley JO, Ye X, Duda DG, et al. Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol. 2016;34(14):1669–75.CrossRefPubMedPubMedCentral Blakeley JO, Ye X, Duda DG, et al. Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol. 2016;34(14):1669–75.CrossRefPubMedPubMedCentral
178.
go back to reference Dilwali S, Roberts D, Stankovic KM. Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells. Cancer Biol Ther. 2015;16(1):170–5.CrossRefPubMedPubMedCentral Dilwali S, Roberts D, Stankovic KM. Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells. Cancer Biol Ther. 2015;16(1):170–5.CrossRefPubMedPubMedCentral
179.
go back to reference Huang X, Xu J, Shen Y, et al. Protein profiling of cerebrospinal fluid from patients undergoing vestibular schwannoma surgery and clinical significance. Biomed Pharmacother. 2019;116: 108985.CrossRefPubMed Huang X, Xu J, Shen Y, et al. Protein profiling of cerebrospinal fluid from patients undergoing vestibular schwannoma surgery and clinical significance. Biomed Pharmacother. 2019;116: 108985.CrossRefPubMed
181.
go back to reference Early S, Moon IS, Bommakanti K, et al. A novel microneedle device for controlled and reliable liquid biopsy of the human inner ear. Hear Res. 2019;381: 107761.CrossRefPubMed Early S, Moon IS, Bommakanti K, et al. A novel microneedle device for controlled and reliable liquid biopsy of the human inner ear. Hear Res. 2019;381: 107761.CrossRefPubMed
182.
go back to reference Agnihotri S, Jalali S, Wilson MR, et al. The genomic landscape of schwannoma. Nat Genet. 2016;48(11):1339–48.CrossRefPubMed Agnihotri S, Jalali S, Wilson MR, et al. The genomic landscape of schwannoma. Nat Genet. 2016;48(11):1339–48.CrossRefPubMed
Metadata
Title
Gene Therapy for Neurofibromatosis Type 2-Related Schwannomatosis: Recent Progress, Challenges, and Future Directions
Authors
Ruofei Yuan
Bo Wang
Ying Wang
Pinan Liu
Publication date
17-05-2024
Publisher
Springer Healthcare
Published in
Oncology and Therapy / Issue 2/2024
Print ISSN: 2366-1070
Electronic ISSN: 2366-1089
DOI
https://doi.org/10.1007/s40487-024-00279-2

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