{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:09:38Z","timestamp":1792804178668,"version":"4.5.0"},"reference-count":197,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CNPq","award":["406096\/2024-4"],"award-info":[{"award-number":["406096\/2024-4"]}],"id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"crossref"}]},{"name":"CNPq","award":["408763\/2023-0"],"award-info":[{"award-number":["408763\/2023-0"]}],"id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"crossref"}]},{"name":"CNPq","award":["0386\/24"],"award-info":[{"award-number":["0386\/24"]}],"id":[{"id":"https:\/\/ror.org\/03swz6y49","id-type":"ROR","asserted-by":"crossref"}]},{"name":"FINEP","award":["406096\/2024-4"],"award-info":[{"award-number":["406096\/2024-4"]}],"id":[{"id":"https:\/\/ror.org\/030w99567","id-type":"ROR","asserted-by":"crossref"}]},{"name":"FINEP","award":["408763\/2023-0"],"award-info":[{"award-number":["408763\/2023-0"]}],"id":[{"id":"https:\/\/ror.org\/030w99567","id-type":"ROR","asserted-by":"crossref"}]},{"name":"FINEP","award":["0386\/24"],"award-info":[{"award-number":["0386\/24"]}],"id":[{"id":"https:\/\/ror.org\/030w99567","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul (FAPERGS)","award":["406096\/2024-4"],"award-info":[{"award-number":["406096\/2024-4"]}],"id":[{"id":"https:\/\/ror.org\/05k49za97","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul (FAPERGS)","award":["408763\/2023-0"],"award-info":[{"award-number":["408763\/2023-0"]}],"id":[{"id":"https:\/\/ror.org\/05k49za97","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul (FAPERGS)","award":["0386\/24"],"award-info":[{"award-number":["0386\/24"]}],"id":[{"id":"https:\/\/ror.org\/05k49za97","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["406096\/2024-4"],"award-info":[{"award-number":["406096\/2024-4"]}],"id":[{"id":"https:\/\/ror.org\/00x0ma614","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["408763\/2023-0"],"award-info":[{"award-number":["408763\/2023-0"]}],"id":[{"id":"https:\/\/ror.org\/00x0ma614","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brazil (CAPES)","award":["0386\/24"],"award-info":[{"award-number":["0386\/24"]}],"id":[{"id":"https:\/\/ror.org\/00x0ma614","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Pontifical Catholic University of Rio Grande do Sul (PUCRS)","award":["406096\/2024-4"],"award-info":[{"award-number":["406096\/2024-4"]}],"id":[{"id":"https:\/\/ror.org\/025vmq686","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Pontifical Catholic University of Rio Grande do Sul (PUCRS)","award":["408763\/2023-0"],"award-info":[{"award-number":["408763\/2023-0"]}],"id":[{"id":"https:\/\/ror.org\/025vmq686","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Pontifical Catholic University of Rio Grande do Sul (PUCRS)","award":["0386\/24"],"award-info":[{"award-number":["0386\/24"]}],"id":[{"id":"https:\/\/ror.org\/025vmq686","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Brain Institute of Rio Grande do Sul (BraIns)","award":["406096\/2024-4"],"award-info":[{"award-number":["406096\/2024-4"]}],"id":[{"id":"https:\/\/ror.org\/007j2dm88","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Brain Institute of Rio Grande do Sul (BraIns)","award":["408763\/2023-0"],"award-info":[{"award-number":["408763\/2023-0"]}],"id":[{"id":"https:\/\/ror.org\/007j2dm88","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Brain Institute of Rio Grande do Sul (BraIns)","award":["0386\/24"],"award-info":[{"award-number":["0386\/24"]}],"id":[{"id":"https:\/\/ror.org\/007j2dm88","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>mTORopathies represent a group of neurodevelopmental disorders linked to dysregulated mTOR signaling, resulting in conditions such as tuberous sclerosis complex, focal cortical dysplasia, hemimegalencephaly, and Smith\u2013Kingsmore Syndrome. These disorders often manifest with epilepsy, cognitive impairments, and, in some cases, structural brain anomalies. The mTOR pathway, a central regulator of cell growth and metabolism, plays a crucial role in brain development, where its hyperactivation leads to abnormal neuroplasticity, tumor formation, and heightened neuronal excitability. Current treatments primarily rely on mTOR inhibitors, such as rapamycin, which reduce seizure frequency and tumor size but fail to address underlying genetic causes. Advances in gene editing, particularly via CRISPR\/Cas9, offer promising avenues for precision therapies targeting the genetic mutations driving mTORopathies. New delivery systems, including viral and non-viral vectors, aim to enhance the specificity and efficacy of these therapies, potentially transforming the management of these disorders. While gene editing holds curative potential, challenges remain concerning delivery, long-term safety, and ethical considerations. Continued research into mTOR mechanisms and innovative gene therapies may pave the way for transformative, personalized treatments for patients affected by these complex neurodevelopmental conditions.<\/jats:p>","DOI":"10.3390\/cells14090662","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:13Z","timestamp":1746185713000},"page":"662","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["mTORopathies in Epilepsy and Neurodevelopmental Disorders: The Future of Therapeutics and the Role of Gene Editing"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3394-9231","authenticated-orcid":false,"given":"Marina Ottmann","family":"Boff","sequence":"first","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"},{"name":"School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9144-6670","authenticated-orcid":false,"given":"Fernando Ant\u00f4nio Costa","family":"Xavier","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"},{"name":"Graduate Program in Medicine and Health Sciences, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7141-2422","authenticated-orcid":false,"given":"Fernando Mendon\u00e7a","family":"Diz","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia Budelon","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Meireles","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"},{"name":"School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Zambeli","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"},{"name":"School of Medicine, University of the Valley of the Rio dos Sinos (UNISINOS), S\u00e3o Leopoldo 93022-750, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2191-7789","authenticated-orcid":false,"given":"Douglas Bottega","family":"Pazzin","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"},{"name":"Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thales Thor Ramos","family":"Previato","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"},{"name":"Graduate Program in Biomedical Gerontology, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena Scartassini","family":"Erwig","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"},{"name":"School of Health and Life, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9294-0486","authenticated-orcid":false,"given":"Jo\u00e3o Ismael Budelon","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda Thays Konat","family":"Bruzzo","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Marinowic","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"},{"name":"School of Health and Life, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6776-1515","authenticated-orcid":false,"given":"Jaderson Costa","family":"da Costa","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1986-973X","authenticated-orcid":false,"given":"Gabriele","family":"Zanirati","sequence":"additional","affiliation":[{"name":"Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.ajpath.2018.11.013","article-title":"Mammalian Target of Rapamycin: A Metabolic Rheostat for Regulating Adipose Tissue Function and Cardiovascular Health","volume":"189","author":"Wipperman","year":"2019","journal-title":"Am. J. Pathol."},{"key":"ref_2","unstructured":"Committee, H.G.N. (2025, January 19). MTOR (Mechanistic Target Of Rapamycin Kinase). Available online: https:\/\/www.genenames.org\/data\/gene-symbol-report\/#!\/hgnc_id\/HGNC:3942."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41392-023-01608-z","article-title":"Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease","volume":"8","author":"Panwar","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"721","DOI":"10.7164\/antibiotics.28.721","article-title":"Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle","volume":"28","author":"Vezina","year":"1975","journal-title":"J. Antibiot."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"el Hage, A., and Dormond, O. (2021). Combining mTOR Inhibitors and T Cell-Based Immunotherapies in Cancer Treatment. Cancers, 13.","DOI":"10.3390\/cancers13061359"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1083\/jcb.201610060","article-title":"Localization of mTORC2 activity inside cells","volume":"216","author":"Ebner","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1152\/physrev.00026.2020","article-title":"Regulation and metabolic functions of mTORC1 and mTORC2","volume":"101","author":"Szwed","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cell.2008.11.044","article-title":"Bidirectional transport of amino acids regulates mTOR and autophagy","volume":"136","author":"Nicklin","year":"2009","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/ncb1753","article-title":"Regulation of TORC1 by Rag GTPases in nutrient response","volume":"10","author":"Kim","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/ncb1183","article-title":"Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive","volume":"6","author":"Jacinto","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/j.ccell.2017.11.011","article-title":"mTORC2 Promotes Tumorigenesis via Lipid Synthesis","volume":"32","author":"Guri","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41580-019-0199-y","article-title":"mTOR at the nexus of nutrition, growth, ageing and disease","volume":"21","author":"Liu","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13023-024-03495-1","article-title":"Long-term neuropsychologic outcome of pre-emptive mTOR inhibitor treatment in children with tuberous sclerosis complex (TSC) under 4 months of age (PROTECT), a two-arm, randomized, observer-blind, controlled phase IIb national multicentre clinical trial: Study protocol","volume":"20","author":"Driedger","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ryskalin, L., Limanaqi, F., Frati, A., Busceti, C.L., and Fornai, F. (2018). mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082226"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"109203","DOI":"10.1016\/j.neuropharm.2022.109203","article-title":"Sirolimus relieves seizures and neuropsychiatric symptoms via changes of microglial polarity in tuberous sclerosis complex model mice","volume":"218","author":"Fujimoto","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cui, F., Gu, S., Gu, Y., Yin, J., Fang, C., and Liu, L. (2021). Alteration in the mRNA expression profile of the autophagy-related mTOR pathway in schizophrenia patients treated with olanzapine. BMC Psychiatry, 21.","DOI":"10.1186\/s12888-021-03394-w"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1007\/s10787-022-01031-w","article-title":"Role of the NRG1\/ErbB4 and PI3K\/AKT\/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats","volume":"30","author":"Nawwar","year":"2022","journal-title":"Inflammopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.tins.2009.11.003","article-title":"mTOR signaling: At the crossroads of plasticity, memory and disease","volume":"33","author":"Hoeffer","year":"2010","journal-title":"Trends Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1073\/pnas.012605299","article-title":"A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus","volume":"99","author":"Tang","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.neuron.2014.09.034","article-title":"The neurology of mTOR","volume":"84","author":"Lipton","year":"2014","journal-title":"Neuron"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.18632\/oncotarget.3006","article-title":"Rapamycin inhibits mSin1 phosphorylation independently of mTORC1 and mTORC2","volume":"6","author":"Luo","year":"2015","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eaar3938","DOI":"10.1126\/sciadv.aar3938","article-title":"ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer","volume":"4","author":"Harwood","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhan, J., Harwood, F., Have, S.T., Lamond, A., Phillips, A.H., Kriwacki, R.W., Halder, P., Cardone, M., and Grosveld, G.C. (2024). Assembly of mTORC3 Involves Binding of ETV7 to Two Separate Sequences in the mTOR Kinase Domain. Int. J. Mol. Sci., 25.","DOI":"10.1101\/2024.03.19.583970"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9760","DOI":"10.1523\/JNEUROSCI.1427-04.2004","article-title":"Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites","volume":"24","author":"Takei","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"38121","DOI":"10.1074\/jbc.C500363200","article-title":"Glutamatergic regulation of the p70S6 kinase in primary mouse neurons","volume":"280","author":"Lenz","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.tcb.2010.03.004","article-title":"The regulation of energy metabolism and the IGF-1\/mTOR pathways by the p53 protein","volume":"20","author":"Feng","year":"2010","journal-title":"Trends Cell Biol"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2995","DOI":"10.1002\/brb3.2995","article-title":"Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy","volume":"13","author":"Zhao","year":"2023","journal-title":"Brain Behav."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhang, X., Wu, Y., Sun, X., Cui, Q., Bai, X., Dong, G., Gao, Z., Wang, Y., Gao, C., and Sun, S. (2022). The PI3K\/AKT\/mTOR signaling pathway is aberrantly activated in primary central nervous system lymphoma and correlated with a poor prognosis. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09275-z"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.neuron.2006.03.023","article-title":"Pten regulates neuronal arborization and social interaction in mice","volume":"50","author":"Kwon","year":"2006","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1038\/s41591-019-0608-y","article-title":"Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency","volume":"25","author":"Chen","year":"2019","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101021","DOI":"10.1016\/j.gendis.2023.04.041","article-title":"The molecular genetics of PI3K\/PTEN\/AKT\/mTOR pathway in the malformations of cortical development","volume":"11","author":"Ma","year":"2024","journal-title":"Genes Dis."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Girodengo, M., Ultanir, S.K., and Bateman, J.M. (2022). Mechanistic target of rapamycin signaling in human nervous system development and disease. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.1005631"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s13023-022-02266-0","article-title":"Perfect match: mTOR inhibitors and tuberous sclerosis complex","volume":"17","author":"Luo","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gerasimenko, A., Baldassari, S., and Baulac, S. (2023). mTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy. Neurobiol. Dis., 182.","DOI":"10.1016\/j.nbd.2023.106144"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Nguyen, L.H., and Bordey, A. (2021). Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies. Front. Neuroanat., 15.","DOI":"10.3389\/fnana.2021.664695"},{"key":"ref_38","first-page":"100333","article-title":"Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior","volume":"5","author":"Liu","year":"2024","journal-title":"HGG Adv."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Besterman, A.D., Althoff, T., Elfferich, P., Gutierrez-Mejia, I., Sadik, J., Bernstein, J.A., van Ierland, Y., Kattentidt-Mouravieva, A.A., Nellist, M., and Abramson, J. (2021). Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity. PLoS Genet., 17.","DOI":"10.1371\/journal.pgen.1009651"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1002\/ajmg.a.62350","article-title":"Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant","volume":"185","author":"Poole","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1111\/cge.13135","article-title":"mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review","volume":"93","author":"Gordo","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s00401-019-02061-5","article-title":"Dissecting the genetic basis of focal cortical dysplasia: A large cohort study","volume":"138","author":"Baldassari","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.neurol.2022.12.007","article-title":"mTOR-therapy and targeted treatment opportunities in mTOR-related epilepsies associated with cortical malformations","volume":"179","author":"Auvin","year":"2023","journal-title":"Rev. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Lee, W.S., Baldassari, S., Stephenson, S.E.M., Lockhart, P.J., Baulac, S., and Leventer, R.J. (2022). Cortical Dysplasia and the mTOR Pathway: How the Study of Human Brain Tissue Has Led to Insights into Epileptogenesis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031344"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1007\/s00381-006-0149-9","article-title":"Hemimegalencephaly: Clinical implications and surgical treatment","volume":"22","author":"Battaglia","year":"2006","journal-title":"Childs Nerv. Syst."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/epi4.12377","article-title":"mTOR pathway somatic variants and the molecular pathogenesis of hemimegalencephaly","volume":"5","author":"Garcia","year":"2020","journal-title":"Epilepsia Open"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1002\/ajmg.c.31401","article-title":"Megalencephaly and hemimegalencephaly: Breakthroughs in molecular etiology","volume":"166C","author":"Mirzaa","year":"2014","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ejpn.2020.12.007","article-title":"Hemimegalencephaly and tuberous sclerosis complex: A rare yet challenging association","volume":"30","author":"Sidira","year":"2021","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S155","DOI":"10.1016\/j.nephro.2017.02.004","article-title":"[PIK3CA-related overgrowth syndrome (PROS)]","volume":"13","author":"Venot","year":"2017","journal-title":"Nephrol. Ther."},{"key":"ref_50","first-page":"287","article-title":"PIK3CA-related overgrowth spectrum (PROS): Diagnostic and testing eligibility criteria, differential diagnosis, and evaluation","volume":"167A","author":"Rios","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1002\/dneu.22816","article-title":"STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation","volume":"81","author":"Dang","year":"2021","journal-title":"Dev. Neurobiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1111\/j.1528-1167.2012.03506.x","article-title":"Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target","volume":"53","author":"Galanopoulou","year":"2012","journal-title":"Epilepsia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1093\/brain\/awm100","article-title":"Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5","volume":"130","author":"Puffenberger","year":"2007","journal-title":"Brain"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1172\/JCI41592","article-title":"STRADalpha deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice","volume":"120","author":"Orlova","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.ajhg.2019.06.016","article-title":"De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia","volume":"105","author":"Haijes","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.braindev.2022.04.002","article-title":"De novo POLR2A p.(Ile457Thr) variant associated with early-onset encephalopathy and cerebellar atrophy: Expanding the phenotypic spectrum","volume":"44","author":"Giacomini","year":"2022","journal-title":"Brain Dev."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Zhang, Y.Z., Zeb, A., and Cheng, L.F. (2022). Exploring the molecular mechanism of hepatitis virus inducing hepatocellular carcinoma by microarray data and immune infiltrates analysis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1032819"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Kreis, P., Leondaritis, G., Lieberam, I., and Eickholt, B.J. (2014). Subcellular targeting and dynamic regulation of PTEN: Implications for neuronal cells and neurological disorders. Front. Mol. Neurosci., 7.","DOI":"10.3389\/fnmol.2014.00023"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"RP91323","DOI":"10.7554\/eLife.91323.3","article-title":"Hyperactivity of mTORC1- and mTORC2-dependent signaling mediates epilepsy downstream of somatic PTEN loss","volume":"12","author":"Cullen","year":"2024","journal-title":"Elife"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"111574","DOI":"10.1016\/j.celrep.2022.111574","article-title":"Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss","volume":"41","author":"Tariq","year":"2022","journal-title":"Cell Rep."},{"key":"ref_61","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1993). DEPDC5-Related Epilepsy. GeneReviews(\u00ae), University of Washington."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"108678","DOI":"10.1016\/j.yebeh.2022.108678","article-title":"DEPDC5-related epilepsy: A comprehensive review","volume":"130","author":"Samanta","year":"2022","journal-title":"Epilepsy Behav."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.nbd.2017.12.010","article-title":"A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility","volume":"111","author":"Yuskaitis","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1258096","DOI":"10.1126\/science.1258096","article-title":"Genome editing. The new frontier of genome engineering with CRISPR-Cas9","volume":"346","author":"Doudna","year":"2014","journal-title":"Science"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.amjmed.2023.12.018","article-title":"CRISPR Therapy of Sickle Cell Disease: The Dawning of the Gene Editing Era","volume":"137","author":"Adashi","year":"2024","journal-title":"Am. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1056\/NEJMoa2031054","article-title":"CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia","volume":"384","author":"Frangoul","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1126\/science.110.2865.543","article-title":"Sickle cell anemia a molecular disease","volume":"110","author":"Pauling","year":"1949","journal-title":"Science"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1084\/jem.79.2.137","article-title":"Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types: Induction of Transformation by a Desoxyribonucleic Acid Fraction Isolated from Pneumococcus Type Iii","volume":"79","author":"Avery","year":"1944","journal-title":"J. Exp. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/BLO.0b013e31814b9304","article-title":"Molecular structure of nucleic acids: A structure for deoxyribose nucleic acid","volume":"462","author":"Watson","year":"2007","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1084\/jem.137.4.1091","article-title":"Induction of arginase activity with the Shope papilloma virus in tissue culture cells from an argininemic patient","volume":"137","author":"Rogers","year":"1973","journal-title":"J. Exp. Med."},{"key":"ref_71","first-page":"1","article-title":"Unsuccessful trial of gene replacement in arginase deficiency","volume":"119","author":"Terheggen","year":"1975","journal-title":"Z. Kinderheilkd"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1006\/mthe.2001.0486","article-title":"The Cline affair","volume":"4","author":"Beutler","year":"2001","journal-title":"Mol. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1097\/00000658-199310000-00006","article-title":"The development of gene therapy for the treatment of cancer","volume":"218","author":"Rosenberg","year":"1993","journal-title":"Ann. Surg."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.gene.2013.03.137","article-title":"History of gene therapy","volume":"525","author":"Wirth","year":"2013","journal-title":"Gene"},{"key":"ref_75","unstructured":"(2025, January 19). Advanced Therapy Medicinal Products: Overview. Available online: https:\/\/www.ema.europa.eu\/en\/human-regulatory-overview\/advanced-therapy-medicinal-products-overview."},{"key":"ref_76","unstructured":"(2025, January 19). Available online: https:\/\/www.fda.gov\/."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/dvdy.60","article-title":"New frontiers in modeling tuberous sclerosis with human stem cell-derived neurons and brain organoids","volume":"249","author":"Blair","year":"2020","journal-title":"Dev. Dyn."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"182ra153","DOI":"10.1126\/scitranslmed.3005271","article-title":"Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder","volume":"5","author":"Parker","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.nbd.2016.02.010","article-title":"Depdc5 knockout rat: A novel model of mTORopathy","volume":"89","author":"Marsan","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1038\/npp.2015.339","article-title":"Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice","volume":"41","author":"Cupolillo","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s12519-022-00576-8","article-title":"Modeling tuberous sclerosis complex with human induced pluripotent stem cells","volume":"20","author":"Niu","year":"2024","journal-title":"World J. Pediatr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.nbd.2015.04.018","article-title":"Survival benefit and phenotypic improvement by hamartin gene therapy in a tuberous sclerosis mouse brain model","volume":"82","author":"Prabhakar","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.omtm.2019.08.003","article-title":"Long-Term Therapeutic Efficacy of Intravenous AAV-Mediated Hamartin Replacement in Mouse Model of Tuberous Sclerosis Type 1","volume":"15","author":"Prabhakar","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"eabb1703","DOI":"10.1126\/sciadv.abb1703","article-title":"Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin","volume":"7","author":"Cheah","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41573-020-0090-8","article-title":"Engineering precision nanoparticles for drug delivery","volume":"20","author":"Mitchell","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"115346","DOI":"10.1016\/j.addr.2024.115346","article-title":"Exploring the potential of cell-derived vesicles for transient delivery of gene editing payloads","volume":"211","author":"Leandro","year":"2024","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/ana.25272","article-title":"Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA","volume":"84","author":"Hu","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1093\/hmg\/ddaa068","article-title":"Prevention of premature death and seizures in a Depdc5 mouse epilepsy model through inhibition of mTORC1","volume":"29","author":"Klofas","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"8762","DOI":"10.1073\/pnas.151033798","article-title":"A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice","volume":"98","author":"Kobayashi","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5546","DOI":"10.1523\/JNEUROSCI.5540-06.2007","article-title":"A mouse model of tuberous sclerosis: Neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival","volume":"27","author":"Meikle","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.nbd.2011.08.024","article-title":"Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin","volume":"45","author":"Carson","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.neuron.2013.03.017","article-title":"Excitatory\/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis","volume":"78","author":"Bateup","year":"2013","journal-title":"Neuron"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.nbd.2012.10.014","article-title":"Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex","volume":"51","author":"Reith","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1172\/JCI44909","article-title":"Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice","volume":"121","author":"Feliciano","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1523\/JNEUROSCI.2260-18.2019","article-title":"mTOR Hyperactivity Levels Influence the Severity of Epilepsy and Associated Neuropathology in an Experimental Model of Tuberous Sclerosis Complex and Focal Cortical Dysplasia","volume":"39","author":"Nguyen","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1038\/s41591-018-0139-y","article-title":"Genetically engineered human cortical spheroid models of tuberous sclerosis","volume":"24","author":"Blair","year":"2018","journal-title":"Nat. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.celrep.2016.02.090","article-title":"mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis","volume":"15","author":"Costa","year":"2016","journal-title":"Cell Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.stem.2016.11.017","article-title":"Induction of Expansion and Folding in Human Cerebral Organoids","volume":"20","author":"Li","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"113432","DOI":"10.1016\/j.expneurol.2020.113432","article-title":"Dynamic analysis of 4E-BP1 phosphorylation in neurons with Tsc2 or Depdc5 knockout","volume":"334","author":"Iffland","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1126\/science.1225829","article-title":"A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity","volume":"337","author":"Jinek","year":"2012","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"Ran","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1146\/annurev.genet.40.110405.090451","article-title":"DNA double-strand break repair: All\u2019s well that ends well","volume":"40","author":"Wyman","year":"2006","journal-title":"Annu. Rev. Genet."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.semcancer.2019.07.003","article-title":"mTOR: Role in cancer, metastasis and drug resistance","volume":"59","author":"Murugan","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"eaay2940","DOI":"10.1126\/scisignal.aay2940","article-title":"Cracking the context-specific PI3K signaling code","volume":"13","author":"Madsen","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Redenbaugh, V., and Coulter, T. (2021). Disorders Related to PI3Kdelta Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.702872"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1038\/s41374-022-00821-8","article-title":"Oncogenic potential of PIK3CD in glioblastoma is exerted through cytoskeletal proteins PAK3 and PLEK2","volume":"102","author":"Shao","year":"2022","journal-title":"Lab. Investig."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.chembiol.2022.02.006","article-title":"Rheb regulates nuclear mTORC1 activity independent of farnesylation","volume":"29","author":"Zhong","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","article-title":"AKT\/PKB Signaling: Navigating the Network","volume":"169","author":"Manning","year":"2017","journal-title":"Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/nature17946","article-title":"Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage","volume":"533","author":"Komor","year":"2016","journal-title":"Nature"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/s41576-022-00541-1","article-title":"Prime editing for precise and highly versatile genome manipulation","volume":"24","author":"Chen","year":"2023","journal-title":"Nat. Rev. Genet."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41587-021-01039-7","article-title":"Engineered pegRNAs improve prime editing efficiency","volume":"40","author":"Nelson","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41576-018-0059-1","article-title":"Base editing: Precision chemistry on the genome and transcriptome of living cells","volume":"19","author":"Rees","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ccell.2017.01.014","article-title":"A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma","volume":"31","author":"Fan","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.12688\/f1000research.9207.1","article-title":"mTOR inhibitors in cancer therapy","volume":"5","author":"Xie","year":"2016","journal-title":"F1000Research"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"eabe0161","DOI":"10.1126\/scisignal.abe0161","article-title":"Dissecting the biology of mTORC1 beyond rapamycin","volume":"14","author":"Yang","year":"2021","journal-title":"Sci. Signal"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1093\/brain\/awad387","article-title":"Anti-seizure gene therapy for focal cortical dysplasia","volume":"147","author":"Graham","year":"2024","journal-title":"Brain"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Lee, S.H.S., Lee, J.Y., Choi, J.S., Kim, H.J., Kim, J., Cha, S., Lee, K.J., Woo, H.N., Park, K., and Lee, H. (2022). mTOR inhibition as a novel gene therapeutic strategy for diabetic retinopathy. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0269951"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/2211-5463.13281","article-title":"AAV expressing an mTOR-inhibiting siRNA exhibits therapeutic potential in retinal vascular disorders by preserving endothelial integrity","volume":"12","author":"Cha","year":"2022","journal-title":"FEBS Open Bio"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Karar, J., and Maity, A. (2011). PI3K\/AKT\/mTOR Pathway in Angiogenesis. Front. Mol. Neurosci., 4.","DOI":"10.3389\/fnmol.2011.00051"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41573-019-0012-9","article-title":"Adeno-associated virus vector as a platform for gene therapy delivery","volume":"18","author":"Wang","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1743-422X-2-43","article-title":"Adeno-associated virus: From defective virus to effective vector","volume":"2","author":"Goncalves","year":"2005","journal-title":"Virol. J."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1089\/hum.2022.037","article-title":"Cell-Selective Adeno-Associated Virus-Mediated SCN1A Gene Regulation Therapy Rescues Mortality and Seizure Phenotypes in a Dravet Syndrome Mouse Model and Is Well Tolerated in Nonhuman Primates","volume":"33","author":"Tanenhaus","year":"2022","journal-title":"Hum. Gene Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.omtm.2021.04.007","article-title":"The impact of lentiviral vector genome size and producer cell genomic to gag-pol mRNA ratios on packaging efficiency and titre","volume":"21","author":"Sweeney","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Parr-Brownlie, L.C., Bosch-Bouju, C., Schoderboeck, L., Sizemore, R.J., Abraham, W.C., and Hughes, S.M. (2015). Lentiviral vectors as tools to understand central nervous system biology in mammalian model organisms. Front. Mol. Neurosci., 8.","DOI":"10.3389\/fnmol.2015.00014"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"R2","DOI":"10.1093\/hmg\/ddr141","article-title":"Large-scale recombinant adeno-associated virus production","volume":"20","author":"Kotin","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41434-023-00399-w","article-title":"Combinatorial gene therapy for epilepsy: Gene sequence positioning and AAV serotype influence expression and inhibitory effect on seizures","volume":"30","author":"Melin","year":"2023","journal-title":"Gene Ther."},{"key":"ref_127","first-page":"21","article-title":"Gene therapy for Dravet syndrome: Promises and impact on disease trigger and secondary modifications","volume":"3","author":"Massimino","year":"2024","journal-title":"Rare Dis. Orphan Drugs J."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Ding, J., Li, X., Tian, H., Wang, L., Guo, B., Wang, Y., Li, W., Wang, F., and Sun, T. (2021). SCN1A Mutation-Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.743726"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Yu, Z., Zhang, M., Luo, B., Jing, H., Yu, Y., Wang, S., and Luo, S. (2020). Lrp4 in hippocampal astrocytes serves as a negative feedback factor in seizures. Cell Biosci., 10.","DOI":"10.1186\/s13578-020-00498-w"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"eaaw1564","DOI":"10.1126\/scitranslmed.aaw1564","article-title":"Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism","volume":"13","author":"Ng","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Huang, S. (2020). mTOR Signaling in Metabolism and Cancer. Cells, 9.","DOI":"10.3390\/cells9102278"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"3715","DOI":"10.1158\/1078-0432.CCR-23-3874","article-title":"Safety, Efficacy, and Biological Data of T-Cell-Enabling Oncolytic Adenovirus TILT-123 in Advanced Solid Cancers from the TUNIMO Monotherapy Phase I Trial","volume":"30","author":"Pakola","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"e008999","DOI":"10.1136\/jitc-2024-008999","article-title":"Preliminary efficacy and safety of YSCH-01 in patients with advanced solid tumors: An investigator-initiated trial","volume":"12","author":"He","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1016\/j.ymthe.2019.07.015","article-title":"Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers","volume":"27","author":"Haas","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/1531-8249(200007)48:1<27::AID-ANA6>3.0.CO;2-6","article-title":"Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease","volume":"48","author":"Leone","year":"2000","journal-title":"Ann. Neurol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1089\/hum.2004.15.1131","article-title":"Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis","volume":"15","author":"Crystal","year":"2004","journal-title":"Hum. Gene Ther."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/jgm.885","article-title":"Immune responses to AAV in a phase I study for Canavan disease","volume":"8","author":"McPhee","year":"2006","journal-title":"J. Gene Med."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1089\/hum.2008.022","article-title":"Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA","volume":"19","author":"Worgall","year":"2008","journal-title":"Hum. Gene Ther."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Tong, J., Buch, S., Yao, H., Wu, C., Tong, H.I., Wang, Y., and Lu, Y. (2014). Monocytes-derived macrophages mediated stable expression of human brain-derived neurotrophic factor, a novel therapeutic strategy for neuroAIDS. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0082030"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/S0140-6736(16)30374-9","article-title":"Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: An ad-hoc analysis of a non-randomised, open-label, phase 1\/2 trial","volume":"388","author":"Sessa","year":"2016","journal-title":"Lancet"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"119142","DOI":"10.1016\/j.lfs.2021.119142","article-title":"Challenges in adeno-associated virus-based treatment of central nervous system diseases through systemic injection","volume":"270","author":"Huang","year":"2021","journal-title":"Life Sci."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.brainresbull.2019.05.024","article-title":"Challenges of gene delivery to the central nervous system and the growing use of biomaterial vectors","volume":"150","author":"Puhl","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.nbd.2011.09.014","article-title":"Viral vectors for gene delivery to the central nervous system","volume":"48","author":"Lentz","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Spunde, K., Korotkaja, K., and Zajakina, A. (2022). Recombinant Viral Vectors for Therapeutic Programming of Tumour Microenvironment: Advantages and Limitations. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092142"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"e55","DOI":"10.1002\/mog2.55","article-title":"Viral vector-based cancer treatment and current clinical applications","volume":"2","author":"Xie","year":"2023","journal-title":"MedComm Oncol."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Lu, X., Zhang, M., Li, G., Zhang, S., Zhang, J., Fu, X., and Sun, F. (2023). Applications and Research Advances in the Delivery of CRISPR\/Cas9 Systems for the Treatment of Inherited Diseases. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202307.0504.v1"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"e2307796121","DOI":"10.1073\/pnas.2307796121","article-title":"Targeted nonviral delivery of genome editors in vivo","volume":"121","author":"Tsuchida","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"105338","DOI":"10.1016\/j.jddst.2024.105338","article-title":"Principles of CRISPR-Cas9 technology: Advancements in genome editing and emerging trends in drug delivery","volume":"92","author":"Aljabali","year":"2024","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.7150\/thno.92133","article-title":"Small extracellular vesicles (sEVs)-based gene delivery platform for cell-specific CRISPR\/Cas9 genome editing","volume":"14","author":"Dubey","year":"2024","journal-title":"Theranostics"},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Malik, S., Muhammad, K., and Waheed, Y. (2023). Emerging Applications of Nanotechnology in Healthcare and Medicine. Molecules, 28.","DOI":"10.3390\/molecules28186624"},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Malik, S., Muhammad, K., and Waheed, Y. (2023). Nanotechnology: A Revolution in Modern Industry. Molecules, 28.","DOI":"10.3390\/molecules28020661"},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Villa, F., Quarto, R., and Tasso, R. (2019). Extracellular Vesicles as Natural, Safe and Efficient Drug Delivery Systems. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11110557"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.2147\/IJN.S446224","article-title":"Extracellular Vesicles: A New Star for Gene Drug Delivery","volume":"19","author":"Sun","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41392-024-01735-1","article-title":"Extracellular vesicles as tools and targets in therapy for diseases","volume":"9","author":"Kumar","year":"2024","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Zanirati, G., Dos Santos, P.G., Alcara, A.M., Bruzzo, F., Ghilardi, I.M., Wietholter, V., Xavier, F.A.C., Goncalves, J.I.B., Marinowic, D., and Shetty, A.K. (2024). Extracellular Vesicles: The Next Generation of Biomarkers and Treatment for Central Nervous System Diseases. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202404.1717.v1"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Chenthamara, D., Subramaniam, S., Ramakrishnan, S.G., Krishnaswamy, S., Essa, M.M., Lin, F.H., and Qoronfleh, M.W. (2019). Therapeutic efficacy of nanoparticles and routes of administration. Biomater. Res., 23.","DOI":"10.1186\/s40824-019-0166-x"},{"key":"ref_157","doi-asserted-by":"crossref","unstructured":"Yusuf, A., Almotairy, A.R.Z., Henidi, H., Alshehri, O.Y., and Aldughaim, M.S. (2023). Nanoparticles as Drug Delivery Systems: A Review of the Implication of Nanoparticles\u2019 Physicochemical Properties on Responses in Biological Systems. Polymers, 15.","DOI":"10.3390\/polym15071596"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.jconrel.2022.10.061","article-title":"Mechanisms and challenges of nanocarriers as non-viral vectors of therapeutic genes for enhanced pulmonary delivery","volume":"352","author":"Wang","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Witika, B.A., Makoni, P.A., Matafwali, S.K., Chabalenge, B., Mwila, C., Kalungia, A.C., Nkanga, C.I., Bapolisi, A.M., and Walker, R.B. (2020). Biocompatibility of Biomaterials for Nanoencapsulation: Current Approaches. Nanomaterials, 10.","DOI":"10.3390\/nano10091649"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.bbagen.2010.04.007","article-title":"Toxicology of engineered nanomaterials: Focus on biocompatibility, biodistribution and biodegradation","volume":"1810","author":"Kunzmann","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Jia, Y., Jiang, Y., He, Y., Zhang, W., Zou, J., Magar, K.T., Boucetta, H., Teng, C., and He, W. (2023). Approved Nanomedicine against Diseases. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15030774"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Akombaetwa, N., Ilangala, A.B., Thom, L., Memvanga, P.B., Witika, B.A., and Buya, A.B. (2023). Current Advances in Lipid Nanosystems Intended for Topical and Transdermal Drug Delivery Applications. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15020656"},{"key":"ref_163","doi-asserted-by":"crossref","unstructured":"Patra, J.K., Das, G., Fraceto, L.F., Campos, E.V.R., Rodriguez-Torres, M.D.P., Acosta-Torres, L.S., Diaz-Torres, L.A., Grillo, R., Swamy, M.K., and Sharma, S. (2018). Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol., 16.","DOI":"10.1186\/s12951-018-0392-8"},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Yao, Y., Zhou, Y., Liu, L., Xu, Y., Chen, Q., Wang, Y., Wu, S., Deng, Y., Zhang, J., and Shao, A. (2020). Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance. Front. Mol. Biosci., 7.","DOI":"10.3389\/fmolb.2020.00193"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1002\/mog2.67","article-title":"Advances and applications of nanoparticles in cancer therapy","volume":"3","author":"Huang","year":"2024","journal-title":"MedComm Oncol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41392-024-01889-y","article-title":"Current advance of nanotechnology in diagnosis and treatment for malignant tumors","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s11671-021-03628-6","article-title":"Nanoparticles for Cancer Therapy: Current Progress and Challenges","volume":"16","author":"Gavas","year":"2021","journal-title":"Nanoscale Res. Lett."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.ijbiomac.2021.08.076","article-title":"SARS-CoV-2 (Covid-19) vaccines structure, mechanisms and effectiveness: A review","volume":"188","author":"Fathizadeh","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/S1470-2045(19)30326-2","article-title":"NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): A multicentre, phase 2-3, randomised, controlled trial","volume":"20","author":"Bonvalot","year":"2019","journal-title":"Lancet Oncol"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s40120-020-00228-x","article-title":"Correction to: A Review of Patisiran (ONPATTRO(R)) for the Treatment of Polyneuropathy in People with Hereditary Transthyretin Amyloidosis","volume":"10","author":"Urits","year":"2021","journal-title":"Neurol. Ther."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1080\/14740338.2020.1832990","article-title":"A safety evaluation of aripiprazole in the treatment of schizophrenia","volume":"19","author":"Preda","year":"2020","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Anselmo, A.C., and Mitragotri, S. (2019). Nanoparticles in the clinic: An update. Bioeng. Transl. Med., 4.","DOI":"10.1002\/btm2.10143"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.1158\/0008-5472.CAN-05-4007","article-title":"Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy","volume":"66","author":"Drummond","year":"2006","journal-title":"Cancer Res."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ygyno.2019.11.034","article-title":"A randomized phase III trial in patients with recurrent platinum sensitive ovarian cancer comparing efficacy and safety of paclitaxel micellar and Cremophor EL-paclitaxel","volume":"156","author":"Vergote","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"17360","DOI":"10.18632\/oncotarget.14477","article-title":"Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: A systematic review and meta-analysis","volume":"8","author":"Zong","year":"2017","journal-title":"Oncotarget"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s11916-020-00905-4","article-title":"Exparel for Postoperative Pain Management: A Comprehensive Review","volume":"24","author":"Kaye","year":"2020","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_178","first-page":"100854","article-title":"CRISPR\/Cas9 systems: Delivery technologies and biomedical applications","volume":"18","author":"Du","year":"2023","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41392-023-01309-7","article-title":"CRISPR\/Cas9 therapeutics: Progress and prospects","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_180","first-page":"249","article-title":"Gene therapy, early promises, subsequent problems, and recent breakthroughs","volume":"3","author":"Baradaran","year":"2013","journal-title":"Adv. Pharm. Bull."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Wang, C., Pan, C., Yong, H., Wang, F., Bo, T., Zhao, Y., Ma, B., He, W., and Li, M. (2023). Emerging non-viral vectors for gene delivery. J. Nanobiotechnol., 21.","DOI":"10.1186\/s12951-023-02044-5"},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Wallen, M., Aqil, F., Spencer, W., and Gupta, R.C. (2023). Exosomes as an Emerging Plasmid Delivery Vehicle for Gene Therapy. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15071832"},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Butt, M.H., Zaman, M., Ahmad, A., Khan, R., Mallhi, T.H., Hasan, M.M., Khan, Y.H., Hafeez, S., Massoud, E.E.S., and Rahman, M.H. (2022). Appraisal for the Potential of Viral and Nonviral Vectors in Gene Therapy: A Review. Genes, 13.","DOI":"10.3390\/genes13081370"},{"key":"ref_184","unstructured":"Ming, W., and David, G. (2013). Chapter 1: Targeted Gene Delivery: Importance of Administration Routes. Novel Gene Therapy Approaches, IntechOpen."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/978-1-4939-9139-6_8","article-title":"Intravenous Infusion of AAV for Widespread Gene Delivery to the Nervous System","volume":"1950","author":"Gessler","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Saint-Pol, J., Gosselet, F., Duban-Deweer, S., Pottiez, G., and Karamanos, Y. (2020). Targeting and Crossing the Blood-Brain Barrier with Extracellular Vesicles. Cells, 9.","DOI":"10.3390\/cells9040851"},{"key":"ref_187","first-page":"233","article-title":"An overview of nanoparticles in drug delivery: Properties and applications","volume":"46","author":"Hsu","year":"2023","journal-title":"S. Afr. J. Chem. Eng."},{"key":"ref_188","doi-asserted-by":"crossref","unstructured":"Afzal, O., Altamimi, A.S.A., Nadeem, M.S., Alzarea, S.I., Almalki, W.H., Tariq, A., Mubeen, B., Murtaza, B.N., Iftikhar, S., and Riaz, N. (2022). Nanoparticles in Drug Delivery: From History to Therapeutic Applications. Nanomaterials, 12.","DOI":"10.3390\/nano12244494"},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Li, J., Wang, Q., Xia, G., Adilijiang, N., Li, Y., Hou, Z., Fan, Z., and Li, J. (2023). Recent Advances in Targeted Drug Delivery Strategy for Enhancing Oncotherapy. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15092233"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1159\/000515672","article-title":"Current Approaches and Future Directions for the Treatment of mTORopathies","volume":"43","author":"Karalis","year":"2021","journal-title":"Dev. Neurosci."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"fcab222","DOI":"10.1093\/braincomms\/fcab222","article-title":"Epilepsy in the mTORopathies: Opportunities for precision medicine","volume":"3","author":"Moloney","year":"2021","journal-title":"Brain Commun."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.neuron.2019.11.026","article-title":"Therapeutic Targeting of mTORC2 in mTORopathies","volume":"104","author":"Dentel","year":"2019","journal-title":"Neuron"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"e2022120118","DOI":"10.1073\/pnas.2022120118","article-title":"Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction","volume":"118","author":"Condon","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"100015","DOI":"10.1016\/j.bneo.2024.100015","article-title":"Central role of the mTORC1 pathway in glucocorticoid activity against B-ALL cells","volume":"1","author":"Imanaga","year":"2024","journal-title":"Blood Neoplasia"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"e200135","DOI":"10.1212\/NXG.0000000000200135","article-title":"Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies","volume":"10","author":"Coleman","year":"2024","journal-title":"Neurol. Genet."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.omtm.2021.04.001","article-title":"Global regulatory progress in delivering on the promise of gene therapies for unmet medical needs","volume":"21","author":"Drago","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_197","doi-asserted-by":"crossref","unstructured":"Ahmad, A., Munawar, N., Khan, Z., Qusmani, A.T., Khan, S.H., Jamil, A., Ashraf, S., Ghouri, M.Z., Aslam, S., and Mubarik, M.S. (2021). An Outlook on Global Regulatory Landscape for Genome-Edited Crops. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111753"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/9\/662\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:24:53Z","timestamp":1760030693000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/9\/662"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":197,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["cells14090662"],"URL":"https:\/\/doi.org\/10.3390\/cells14090662","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,30]]}}}