- 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;
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
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. |
56. | Pickar-Oliver A, Gersbach CA. The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol, 2019, 20(8): 490-507. |
57. | Zhang X, Wang L, Liu M, et al. CRISPR/Cas9 system: a powerful technology for in vivo and ex vivo gene therapy. Sci China Life Sci, 2017, 60(5): 468-475. |
58. | Komor AC, Kim YB, Packer MS, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 2016, 533(7603): 420-424. |
59. | Zhang X, Zhu B, Chen L, et al. Dual base editor catalyzes both cytosine and adenine base conversions in human cells. Nat Biotechnol, 2020, 38(7): 856-860. |
60. | Chen L, Zhu B, Ru G, et al. Re-engineering the adenine deaminase TadA-8e for efficient and specific CRISPR-based cytosine base editing. Nat Biotechnol, 2023, 41(5): 663-672. |
61. | Chen L, Hong M, Luan C, et al. Adenine transversion editors enable precise, efficient A·T-to-C·G base editing in mammalian cells and embryos. Nat Biotechnol, 2023. doi: 10.1038/s41587-023-01821-9. |
62. | Anzalone AV, Randolph PB, Davis JR, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature, 2019, 576(7785): 149-157. |
63. | Anzalone AV, Koblan LW, Liu DR. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol, 2020, 38(7): 824-844. |
64. | Wu Y, Zeng J, Roscoe BP, et al. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat Med, 2019, 25(5): 776-783. |
65. | Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med, 2021, 384(3): 252-260. |
66. | Everette KA, Newby GA, Levine RM, et al. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Nat Biomed Eng, 2023, 7(5): 616-628. |
67. | Xu S, Luk K, Yao Q, et al. Editing aberrant splice sites efficiently restores β-globin expression in β-thalassemia. Blood, 2019, 133(21): 2255-2262. |
68. | Arbab M, Matuszek Z, Kray KM, et al. Base editing rescue of spinal muscular atrophy in cells and in mice. Science, 2023, 380(6642): eadg6518. |
69. | Chen JR, Chen C, Chen J, et al. Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber's hereditary optic neuropathy. Hum Mol Genet, 2023, 32(9): 1539-1551. |
70. | Leier A, Moore M, Liu H, et al. Targeted exon skipping of NF1 exon 17 as a therapeutic for neurofibromatosis type Ⅰ. Mol Ther Nucleic Acids, 2022, 28: 261-278. |
71. | Wang W, Cui XW, Gu YH, et al. Combined cyclin-dependent kinase inhibition overcomes MAPK/extracellular signal-regulated kinase kinase inhibitor resistance in plexiform neurofibroma of neurofibromatosis type Ⅰ. J Invest Dermatol, 2022, 142(3 Pt A): 613-623. |
72. | Kershner LJ, Choi K, Wu J, et al. Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment. JCI Insight, 2022, 7(18): e154513. |
73. | Mazuelas H, Magallón-Lorenz M, Fernández-Rodríguez J, et al. Modeling iPSC-derived human neurofibroma-like tumors in mice uncovers the heterogeneity of Schwann cells within plexiform neurofibromas. Cell Rep, 2022, 38(7): 110385. |
74. | Le LQ, Liu C, Shipman T, et al. Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. Cancer Res, 2011, 71(13): 4686-4695. |
75. | Maro GS, Vermeren M, Voiculescu O, et al. Neural crest boundary cap cells constitute a source of neuronal and glial cells of the PNS. Nat Neurosci, 2004, 7(9): 930-938. |
76. | Mayes DA, Rizvi TA, Cancelas JA, et al. Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer Res, 2011, 71(13): 4675-4685. |
- 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.
- 56. Pickar-Oliver A, Gersbach CA. The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol, 2019, 20(8): 490-507.
- 57. Zhang X, Wang L, Liu M, et al. CRISPR/Cas9 system: a powerful technology for in vivo and ex vivo gene therapy. Sci China Life Sci, 2017, 60(5): 468-475.
- 58. Komor AC, Kim YB, Packer MS, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 2016, 533(7603): 420-424.
- 59. Zhang X, Zhu B, Chen L, et al. Dual base editor catalyzes both cytosine and adenine base conversions in human cells. Nat Biotechnol, 2020, 38(7): 856-860.
- 60. Chen L, Zhu B, Ru G, et al. Re-engineering the adenine deaminase TadA-8e for efficient and specific CRISPR-based cytosine base editing. Nat Biotechnol, 2023, 41(5): 663-672.
- 61. Chen L, Hong M, Luan C, et al. Adenine transversion editors enable precise, efficient A·T-to-C·G base editing in mammalian cells and embryos. Nat Biotechnol, 2023. doi: 10.1038/s41587-023-01821-9.
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