Gene therapy strategies and prospects for neurofibromatosis type 1_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHENG Tingting ^1,2 , ZHU Beiyao ^1,2 , WANG Zhichao ^1,2 ,  LI Qingfeng ^1,2

1. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China;
2. Neurofibromatosis Type 1 Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China;

Corresponding author：

LI Qingfeng, Email: dr.liqingfeng@shsmu.edu.cn

Keywords：

Neurofibromatosis type 1; NF1 gene; transgenic therapy; gene editing

DOI：

10.7507/1002-1892.202309071

Video：

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Objective To summarize the gene therapy strategies for neurofibromatosis type 1 (NF1) and related research progress. Methods The recent literature on gene therapy for NF1 at home and abroad was reviewed. The structure and function of the NF1 gene and its mutations were analyzed, and the current status as well as future prospects of the transgenic therapy and gene editing strategies were summarized. Results NF1 is an autosomal dominantly inherited tumor predisposition syndrome caused by mutations in the NF1 tumor suppressor gene, which impair the function of the neurofibromin and lead to the disease. It has complex clinical manifestations and is not yet curable. Gene therapy strategies for NF1 are still in the research and development stage. Existing studies on the transgenic therapy for NF1 have mainly focused on the construction and expression of the GTPase-activating protein-related domain in cells that lack of functional neurofibromin, confirming the feasibility of the transgenic therapy for NF1. Future research may focus on split adeno-associated virus (AAV) gene delivery, oversized AAV gene delivery, and the development of new vectors for targeted delivery of full-length NF1 cDNA. In addition, the gene editing tools of the new generation have great potential to treat monogenic genetic diseases such as NF1, but need to be further validated in terms of efficiency and safety. Conclusion Gene therapy, including both the transgenic therapy and gene editing, is expected to become an important new therapeutic approach for NF1 patients.

Citation： ZHENG Tingting, ZHU Beiyao, WANG Zhichao, LI Qingfeng. Gene therapy strategies and prospects for neurofibromatosis type 1. Chinese Journal of Reparative and Reconstructive Surgery, 2024, 38(1): 1-8. doi: 10.7507/1002-1892.202309071 Copy

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1. Ly KI, Blakeley JO. The diagnosis and management of neurofibromatosis type 1. Med Clin North Am, 2019, 103(6): 1035-1054.
2. Wang W, Wei CJ, Cui XW, et al. Impacts of NF1 gene mutations and genetic modifiers in neurofibromatosis type 1. Front Neurol, 2021, 12: 704639.
3. Angelova-Toshkina D, Holzapfel J, Huber S, et al. Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents. Genet Med, 2022, 24(9): 1978-1985.
4. Wang ZC, Li HB, Wei CJ, et al. Community-boosted neurofibromatosis research in China. Lancet Neurol, 2022, 21(9): 773-774.
5. Ge LL, Xing MY, Zhang HB, et al. Role of nerves in neurofibromatosis type 1-related nervous system tumors. Cell Oncol (Dordr), 2022, 45(6): 1137-1153.
6. Chung MH, Aimaier R, Yu Q, et al. RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST. Cell Oncol (Dordr), 2023, 46(5): 1399-1413.
7. Acar S, Armstrong AE, Hirbe AC. Plexiform neurofibroma: shedding light on the investigational agents in clinical trials. Expert Opin Investig Drugs, 2022, 31(1): 31-40.
8. Somatilaka BN, Sadek A, McKay RM, et al. Malignant peripheral nerve sheath tumor: models, biology, and translation. Oncogene, 2022, 41(17): 2405-2421.
9. Cortes-Ciriano I, Steele CD, Piculell K, et al. Genomic patterns of malignant peripheral nerve sheath tumor (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA. Cancer Discov, 2023, 13(3): 654-671.
10. Ece Solmaz A, Isik E, Atik T, et al. Mutation spectrum of the NF1 gene and genotype-phenotype correlations in Turkish patients: Seventeen novel pathogenic variants. Clin Neurol Neurosurg, 2021, 208: 106884.
11. Thomas L, Richards M, Mort M, et al. Assessment of the potential pathogenicity of missense mutations identified in the GTPase-activating protein (GAP)-related domain of the neurofibromatosis type-1 (NF1) gene. Hum Mutat, 2012, 33(12): 1687-1696.
12. Lu D, Nounou R, Beran M, et al. The prognostic significance of bone marrow levels of neurofibromatosis-1 protein and ras oncogene mutations in patients with acute myeloid leukemia and myelodysplastic syndrome. Cancer, 2003, 97(2): 441-449.
13. Shilyansky C, Lee YS, Silva AJ. Molecular and cellular mechanisms of learning disabilities: a focus on NF1. Annu Rev Neurosci, 2010, 33: 221-243.
14. Philpott C, Tovell H, Frayling IM, et al. The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics, 2017, 11(1): 13.
15. Báez-Flores J, Rodríguez-Martín M, Lacal J. The therapeutic potential of neurofibromin signaling pathways and binding partners. Commun Biol, 2023, 6(1): 436.
16. Hsueh YP. From neurodevelopment to neurodegeneration: the interaction of neurofibromin and valosin-containing protein/p97 in regulation of dendritic spine formation. J Biomed Sci, 2012, 19(1): 33.
17. Upadhyaya M, Osborn MJ, Maynard J, et al. Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. Hum Genet, 1997, 99(1): 88-92.
18. Tokuo H, Yunoue S, Feng L, et al. Phosphorylation of neurofibromin by cAMP-dependent protein kinase is regulated via a cellular association of N(G), N(G)-dimethylarginine dimethylaminohydrolase. FEBS Lett, 2001, 494(1-2): 48-53.
19. Peduto C, Zanobio M, Nigro V, et al. Neurofibromatosis type 1: Pediatric aspects and review of genotype-phenotype correlations. Cancers (Basel), 2023, 15(4): 1217.
20. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell, 2017, 170(1): 17-33.
21. Jones DT, Hutter B, Jäger N, et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet, 2013, 45(8): 927-932.
22. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 2008, 455(7216): 1061-1068.
23. Wang HF, Shih YT, Chen CY, et al. Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. J Clin Invest, 2011, 121(12): 4820-4837.
24. Lin YL, Lei YT, Hong CJ, et al. Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway. J Cell Biol, 2007, 177(5): 829-841.
25. Kweh F, Zheng M, Kurenova E, et al. Neurofibromin physically interacts with the N-terminal domain of focal adhesion kinase. Mol Carcinog, 2009, 48(11): 1005-1017.
26. Mangoura D, Sun Y, Li C, et al. Phosphorylation of neurofibromin by PKC is a possible molecular switch in EGF receptor signaling in neural cells. Oncogene, 2006, 25(5): 735-745.
27. Napolitano F, Dell’Aquila M, Terracciano C, et al. Genotype-phenotype correlations in neurofibromatosis type 1: Identification of novel and recurrent NF1 gene variants and correlations with neurocognitive phenotype. Genes (Basel), 2022, 13(7): 1130.
28. Fadhlullah SFB, Halim NBA, Yeo JYT, et al. Pathogenic mutations in neurofibromin identifies a leucine-rich domain regulating glioma cell invasiveness. Oncogene, 2019, 38(27): 5367-5380.
29. Ko JM, Sohn YB, Jeong SY, et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol, 2013, 48(6): 447-453.
30. Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med, 2010, 12(1): 1-11.
31. Koczkowska M, Chen Y, Callens T, et al. Genotype-phenotype correlation in NF1: Evidence for a more severe phenotype associated with missense mutations affecting NF1 codons 844-848. Am J Hum Genet, 2018, 102(1): 69-87.
32. Koczkowska M, Callens T, Chen Y, et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p. Met1149, p. Arg1276, and p. Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat, 2020, 41(1): 299-315.
33. Kehrer-Sawatzki H, Cooper DN. Classification of NF1 microdeletions and its importance for establishing genotype/phenotype correlations in patients with NF1 microdeletions. Hum Genet, 2021, 140(12): 1635-1649.
34. Pasmant E, Sabbagh A, Spurlock G, et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat, 2010, 31(6): E1506-E1518.
35. Pacot L, Vidaud D, Sabbagh A, et al. Severe phenotype in patients with large deletions of NF1. Cancers (Basel), 2021, 13(12): 2963.
36. Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet, 2007, 80(1): 140-151.
37. Koczkowska M, Callens T, Gomes A, et al. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med, 2019, 21(4): 867-876.
38. Rojnueangnit K, Xie J, Gomes A, et al. High incidence of noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: Genotype-Phenotype Correlation. Hum Mutat, 2015, 36(11): 1052-1063.
39. Scala M, Schiavetti I, Madia F, et al. Genotype-phenotype correlations in neurofibromatosis type 1: A single-center cohort study. Cancers (Basel), 2021, 13(8): 1879.
40. Shao L, Shi R, Zhao Y, et al. Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products. J Transl Med, 2022, 20(1): 514.
41. Li X, Le Y, Zhang Z, et al. Viral vector-based gene therapy. Int J Mol Sci, 2023, 24(9): 7736.
42. Bulcha JT, Wang Y, Ma H, et al. Viral vector platforms within the gene therapy landscape. Signal Transduct Target Ther, 2021, 6(1): 53.
43. Hiatt KK, Ingram DA, Zhang Y, et al. Neurofibromin GTPase-activating protein-related domains restore normal growth in Nf1^−/− cells. J Biol Chem, 2001, 276(10): 7240-7245.
44. Thomas SL, Deadwyler GD, Tang J, et al. Reconstitution of the NF1 GAP-related domain in NF1-deficient human Schwann cells. Biochem Biophys Res Commun, 2006, 348(3): 971-980.
45. Bodempudi V, Yamoutpoor F, Pan W, et al. Ral overactivation in malignant peripheral nerve sheath tumors. Mol Cell Biol, 2009, 29(14): 3964-3974.
46. Bai RY, Esposito D, Tam AJ, et al. Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. Gene Ther, 2019, 26(6): 277-286.
47. Cui XW, Ren JY, Gu YH, et al. NF1, neurofibromin and gene therapy: Prospects of next-generation therapy. Curr Gene Ther, 2020, 20(2): 100-108.
48. Patel A, Zhao J, Duan D, et al. Design of AAV vectors for delivery of large or multiple transgenes. Methods Mol Biol, 2019, 1950: 19-33.
49. Akil O, Dyka F, Calvet C, et al. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proc Natl Acad Sci U S A, 2019, 116(10): 4496-4501.
50. Al-Moyed H, Cepeda AP, Jung S, et al. A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice. EMBO Mol Med, 2019, 11(1): e9396.
51. Maddalena A, Tornabene P, Tiberi P, et al. Triple vectors expand AAV transfer capacity in the retina. Mol Ther, 2018, 26(2): 524-541.
52. McClements ME, Barnard AR, Singh MS, et al. An AAV dual vector strategy ameliorates the stargardt phenotype in adult Abca4^−/− mice. Hum Gene Ther, 2019, 30(5): 590-600.
53. Reisinger E. Dual-AAV delivery of large gene sequences to the inner ear. Hear Res, 2020, 394: 107857.
54. Grieger JC, Samulski RJ. Packaging capacity of adeno-associated virus serotypes: impact of larger genomes on infectivity and postentry steps. J Virol, 2005, 79(15): 9933-9944.
55. Yan Z, Keiser NW, Song Y, et al. A novel chimeric adenoassociated virus 2/human bocavirus 1 parvovirus vector efficiently transduces human airway epithelia. Mol Ther, 2013, 21(12): 2181-2194.
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