Skip to content
2000
image of Unraveling Etiological Indications and Therapeutic Implications of Familial Cerebral Cavernous Malformations in the Dawn of Gene Therapy for Monogenic Conditions
file format pdf download PDF

Abstract

Cerebral Cavernous Malformations (CCMs) are vascular anomalies in the central nervous system that arise from both genetic and non-genetic factors, and can cause hemorrhage, seizures, and neurological deficits. Approximately 80% of CCMs are sporadic, while 20% are Familial (FCCMs), an autosomal dominant, monogenic disorder characterized by multiple lesions and severe clinical manifestations. Over the past three decades, linkage analyses have identified , , and as major pathogenic genes in FCCMs. However, existing surgical and pharmacological treatments have not adequately prevented disease progression, underscoring the need for more effective strategies. Recent advancements in gene editing tools and delivery systems have transformed gene therapy from a laboratory concept to a clinical reality, offering renewed hope for FCCM patients. Given the multifactorial nature, complexity, and neurological comorbidities of FCCMs, exploring non-surgical gene therapies provides a promising approach for addressing these cerebrovascular lesions. This review summarizes the latest progress in gene editing for FCCMs and examines its therapeutic potential, while acknowledging both the promising benefits and the remaining uncertainties in this evolving field.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cgt/10.2174/0115665232386151250812105845
2025-08-19
2025-10-30

  • From This Site

    /content/journals/cgt/10.2174/0115665232386151250812105845
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cgt/10.2174/0115665232386151250812105845/BMS-CGT-2025-HT49-6632-1.html?itemId=/content/journals/cgt/10.2174/0115665232386151250812105845&mimeType=html&fmt=ahah

References

  1. Flemming K.D. Graff-Radford J. Aakre J. Population-based prevalence of cerebral cavernous malformations in older adults. JAMA Neurol. 2017 74 7 801 805 10.1001/jamaneurol.2017.0439 28492932
    [Google Scholar]
  2. Dalyai R.T. Ghobrial G. Awad I. Management of incidental cavernous malformations: A review. Neurosurg. Focus 2011 31 6 E5 10.3171/2011.9.FOCUS11211 22133177
    [Google Scholar]
  3. Lanfranconi S. Scola E. Meessen J.M.T.A. Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): A randomised, open-label, blinded-endpoint, phase 2 pilot trial. Lancet Neurol. 2023 22 1 35 44 10.1016/S1474‑4422(22)00409‑4 36403580
    [Google Scholar]
  4. Santos A.N. Rauschenbach L. Saban D. Medication intake and hemorrhage risk in patients with familial cerebral cavernous malformations. J. Neurosurg. 2022 137 4 1088 1094 10.3171/2022.1.JNS212724 35213840
    [Google Scholar]
  5. Kim S. Moon J. Jung K.H. Clinicoradiologic data of familial cerebral cavernous malformation with age‐related disease burden. Ann. Clin. Transl. Neurol. 2023 10 3 373 383 10.1002/acn3.51728 36629374
    [Google Scholar]
  6. Li X. Fisher O.S. Boggon T.J. The cerebral cavernous malformations proteins. Oncotarget 2015 6 32 32279 32280 10.18632/oncotarget.5443 26356566
    [Google Scholar]
  7. Choquet H. Trapani E. Goitre L. Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1. Free Radic. Biol. Med. 2016 92 100 109 10.1016/j.freeradbiomed.2016.01.008 26795600
    [Google Scholar]
  8. Tang A.T. Sullivan K.R. Hong C.C. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci. Transl. Med. 2019 11 520 eaaw3521 10.1126/scitranslmed.aaw3521 31776290
    [Google Scholar]
  9. Yang C. Nicholas V.H.L. Zhao J. A novel CCM1/KRIT1 heterozygous nonsense mutation (c.1864C>T) associated with familial cerebral cavernous malformation: A genetic insight from an 8-year continuous observational study. J. Mol. Neurosci. 2017 61 4 511 523 10.1007/s12031‑017‑0893‑1 28255959
    [Google Scholar]
  10. Yang C. Zhao J. Wu B. Zhong H. Li Y. Xu Y. Identification of a novel deletion mutation (c.1780delG) and a novel splice-site mutation (c.1412-1G>A) in the CCM1/KRIT1 gene associated with familial cerebral cavernous malformation in the chinese population. J. Mol. Neurosci. 2017 61 1 8 15 10.1007/s12031‑016‑0836‑2 27649701
    [Google Scholar]
  11. Yang C. Wu B. Zhong H. Li Y. Zheng X. Xu Y. A novel CCM1/KRIT1 heterozygous deletion mutation (c.1919delT) in a Chinese family with familial cerebral cavernous malformation. Clin. Neurol. Neurosurg. 2018 164 44 46 10.1016/j.clineuro.2017.11.005 29169046
    [Google Scholar]
  12. Wang X. Liu X. Lee N. Features of a Chinese family with cerebral cavernous malformation induced by a novel CCM1 gene mutation. Chin. Med. J. 2013 126 18 3427 3432 10.3760/cma.j.issn.0366‑6999.20130590 24034083
    [Google Scholar]
  13. Liu W. Liu M. Lu D. A Chinese family with cerebral cavernous malformation caused by a frameshift mutation of the CCM1 gene: A Case report and review of the literature. Front. Neurol. 2022 13 795514 10.3389/fneur.2022.795514 35444609
    [Google Scholar]
  14. Wang H. Pan Y. Zhang Z. A novel KRIT1/CCM1 gene insertion mutation associated with cerebral cavernous malformations in a Chinese family. J. Mol. Neurosci. 2017 61 2 221 226 10.1007/s12031‑017‑0881‑5 28160210
    [Google Scholar]
  15. Zhao Y. Xie L. Li P. A novel CCM1 gene mutation causes cerebral cavernous malformation in a Chinese family. J. Clin. Neurosci. 2011 18 1 61 65 10.1016/j.jocn.2010.04.051 20884211
    [Google Scholar]
  16. Bergametti F. Denier C. Labauge P. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am. J. Hum. Genet. 2005 76 1 42 51 10.1086/426952 15543491
    [Google Scholar]
  17. Couteulx S.L. Jung H.H. Labauge P. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat. Genet. 1999 23 2 189 193 10.1038/13815 10508515
    [Google Scholar]
  18. Fisher O.S. Boggon T.J. Signaling pathways and the cerebral cavernous malformations proteins: Lessons from structural biology. Cell. Mol. Life Sci. 2014 71 10 1881 1892 10.1007/s00018‑013‑1532‑9 24287896
    [Google Scholar]
  19. Li X. Zhang R. Zhang H. Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. J. Biol. Chem. 2010 285 31 24099 24107 10.1074/jbc.M110.128470 20489202
    [Google Scholar]
  20. Zhou Z. Tang A.T. Wong W.Y. Erratum: Corrigendum: Cerebral cavernous malformations arise from endothelial gain of MEKK3–KLF2/4 signalling. Nature 2016 536 7617 488 10.1038/nature18311 27281211
    [Google Scholar]
  21. Weinsheimer S. Nelson J. Abla A.A. Intracranial hemorrhage rate and lesion burden in patients with familial cerebral cavernous malformation. J. Am. Heart Assoc. 2023 12 3 027572 10.1161/JAHA.122.027572 36695309
    [Google Scholar]
  22. Akers A Al-Shahi Salman R A Awad I Synopsis of guidelines for the clinical management of cerebral cavernous malformations: Consensus recommendations based on systematic literature review by the angioma alliance scientific advisory board clinical experts panel. Neurosurgery 2017 80 5 665 680 10.1093/neuros/nyx091 28387823
    [Google Scholar]
  23. Petersen T.A. Morrison L.A. Schrader R.M. Hart B.L. Familial versus sporadic cavernous malformations: Differences in developmental venous anomaly association and lesion phenotype. AJNR Am. J. Neuroradiol. 2010 31 2 377 382 10.3174/ajnr.A1822 19833796
    [Google Scholar]
  24. Moore S.A. Brown R.D. Christianson T.J.H. Flemming K.D. Long-term natural history of incidentally discovered cavernous malformations in a single-center cohort. J. Neurosurg. 2014 120 5 1188 1192 10.3171/2014.1.JNS131619 24628608
    [Google Scholar]
  25. Fox C.K. Nelson J. McCulloch C.E. Seizure incidence rates in Children and adults with familial cerebral cavernous malformations. Neurology 2021 97 12 e1210 e1216 10.1212/WNL.0000000000012569 34389651
    [Google Scholar]
  26. Haasdijk R.A. Cheng C. Maat-Kievit A.J. Duckers H.J. Cerebral cavernous malformations: From molecular pathogenesis to genetic counselling and clinical management. Eur. J. Hum. Genet. 2012 20 2 134 140 10.1038/ejhg.2011.155 21829231
    [Google Scholar]
  27. Mouchtouris N. Chalouhi N. Chitale A. Management of cerebral cavernous malformations: From diagnosis to treatment. ScientificWorldJournal 2015 2015 1 808314 10.1155/2015/808314 25629087
    [Google Scholar]
  28. Al-Shahi R. Bhattacharya J.J. Currie D.G. Prospective, population-based detection of intracranial vascular malformations in adults: The Scottish intracranial vascular malformation study (SIVMS). Stroke 2003 34 5 1163 1169 10.1161/01.STR.0000069018.90456.C9 12702837
    [Google Scholar]
  29. Richardson BT Dibble CF Borikova AL Johnson GL Cerebral cavernous malformation is a vascular disease associated with activated RhoA signaling. bchm 2013 394 1 35 42 10.1515/hsz‑2012‑0243 23096573
    [Google Scholar]
  30. Polster S.P. Stadnik A. Akers A.L. Atorvastatin treatment of cavernous angiomas with symptomatic hemorrhage exploratory proof of concept (AT CASH EPOC) trial. Neurosurgery 2019 85 6 843 853 10.1093/neuros/nyy539 30476251
    [Google Scholar]
  31. Li W. Shenkar R. Detter M.R. Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models. J. Clin. Invest. 2021 131 3 144893 10.1172/JCI144893 33301422
    [Google Scholar]
  32. Shenkar R. Moore T. Benavides C. Propranolol as therapy for cerebral cavernous malformations: A cautionary note. J. Transl. Med. 2022 20 1 160 10.1186/s12967‑022‑03360‑4 35382850
    [Google Scholar]
  33. Sahoo T. Johnson E.W. Thomas J.W. Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum. Mol. Genet. 1999 8 12 2325 2333 10.1093/hmg/8.12.2325 10545614
    [Google Scholar]
  34. Zhang J. Basu S. Rigamonti D. Dietz H.C. Clatterbuck R.E. KRIT1 modulates β1-integrin-mediated endothelial cell proliferatION. Neurosurgery 2008 63 3 571 578 10.1227/01.NEU.0000325255.30268.B0 18812969
    [Google Scholar]
  35. Swamy H. Glading A.J. Contribution of protein–protein interactions to the endothelial-barrier-stabilizing function of KRIT1. J. Cell Sci. 2022 135 2 jcs258816 10.1242/jcs.258816 34918736
    [Google Scholar]
  36. Zhang J. Clatterbuck R.E. Rigamonti D. Chang D.D. Dietz H.C. Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. Hum. Mol. Genet. 2001 10 25 2953 2960 10.1093/hmg/10.25.2953 11741838
    [Google Scholar]
  37. Tebas P. Stein D. Tang W.W. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 2014 370 10 901 910 10.1056/NEJMoa1300662 24597865
    [Google Scholar]
  38. Shahryari A. Saghaeian Jazi M. Mohammadi S. Development and clinical translation of approved gene therapy products for genetic disorders. Front. Genet. 2019 10 868 10.3389/fgene.2019.00868 31608113
    [Google Scholar]
  39. Ma C.C. Wang Z.L. Xu T. He Z.Y. Wei Y.Q. The approved gene therapy drugs worldwide: From 1998 to 2019. Biotechnol. Adv. 2020 40 107502 10.1016/j.biotechadv.2019.107502 31887345
    [Google Scholar]
  40. Li T. Yang Y. Qi H. CRISPR/Cas9 therapeutics: Progress and prospects. Signal Transduct. Target. Ther. 2023 8 1 36 10.1038/s41392‑023‑01309‑7 36646687
    [Google Scholar]
  41. Zafar A. Quadri S.A. Farooqui M. Familial cerebral cavernous malformations. Stroke 2019 50 5 1294 1301 10.1161/STROKEAHA.118.022314 30909834
    [Google Scholar]
  42. Doudna J.A. Charpentier E. The new frontier of genome engineering with CRISPR-Cas9. Science 2014 346 6213 1258096 10.1126/science.1258096 25430774
    [Google Scholar]
  43. Mendell J.R. Al-Zaidy S.A. Rodino-Klapac L.R. Current clinical applications of in vivo gene Therapy with AAVs. Mol. Ther. 2021 29 2 464 488 10.1016/j.ymthe.2020.12.007 33309881
    [Google Scholar]
  44. Breda L. Papp T.E. Triebwasser M.P. In vivo hematopoietic stem cell modification by mRNA delivery. Science 2023 381 6656 436 443 10.1126/science.ade6967 37499029
    [Google Scholar]
  45. Ferrari S. Naldini L. A step toward stem cell engineering in vivo. Science 2023 381 6656 378 379 10.1126/science.adj0997 37499013
    [Google Scholar]
  46. Xu Y. Shrestha N. Préat V. Beloqui A. An overview of in vitro, ex vivo and in vivo models for studying the transport of drugs across intestinal barriers. Adv. Drug Deliv. Rev. 2021 175 113795 10.1016/j.addr.2021.05.005 33989702
    [Google Scholar]
  47. Krolak T. Chan K.Y. Kaplan L. A high-efficiency AAV for endothelial cell transduction throughout the central nervous system. Nat Cardiovasc Res 2022 1 4 389 400 10.1038/s44161‑022‑00046‑4 35571675
    [Google Scholar]
  48. Chen F. Alphonse M. Liu Q. Strategies for nonviral nanoparticle‐based delivery of CRISPR/Cas9 therapeutics. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2020 12 3 1609 10.1002/wnan.1609 31797562
    [Google Scholar]
  49. Weng J. Yang Y. Song D. Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation. Am. J. Hum. Genet. 2021 108 5 942 950 10.1016/j.ajhg.2021.04.005 33891857
    [Google Scholar]
  50. Yang H. Ren S. Yu S. Methods favoring homology-directed repair choice in response to CRISPR/Cas9 induced-double strand breaks. Int. J. Mol. Sci. 2020 21 18 6461 10.3390/ijms21186461 32899704
    [Google Scholar]
  51. Shen S. Loh T.J. Shen H. Zheng X. Shen H. CRISPR as a strong gene editing tool. BMB Rep. 2017 50 1 20 24 10.5483/BMBRep.2017.50.1.128 27616359
    [Google Scholar]
  52. Ran F.A. Hsu P.D. Lin C.Y. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 2013 154 6 1380 1389 10.1016/j.cell.2013.08.021 23992846
    [Google Scholar]
  53. Wu Y. Zhou H. Fan X. Correction of a genetic disease by CRISPR-Cas9-mediated gene editing in mouse spermatogonial stem cells. Cell Res. 2015 25 1 67 79 10.1038/cr.2014.160 25475058
    [Google Scholar]
  54. Fu Y.W. Dai X.Y. Wang W.T. Dynamics and competition of CRISPR–Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing. Nucleic Acids Res. 2021 49 2 969 985 10.1093/nar/gkaa1251 33398341
    [Google Scholar]
  55. Ran F.A. Hsu P.D. Wright J. Agarwala V. Scott D.A. Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 2013 8 11 2281 2308 10.1038/nprot.2013.143 24157548
    [Google Scholar]
  56. Zetsche B. Gootenberg J.S. Abudayyeh O.O. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell 2015 163 3 759 771 10.1016/j.cell.2015.09.038 26422227
    [Google Scholar]
  57. Mao Z. Chen R. Wang X. CRISPR/Cas12a-based technology: A powerful tool for biosensing in food safety. Trends Food Sci. Technol. 2022 122 211 222 10.1016/j.tifs.2022.02.030 35250172
    [Google Scholar]
  58. Komor A.C. Kim Y.B. Packer M.S. Zuris J.A. Liu D.R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 2016 533 7603 420 424 10.1038/nature17946 27096365
    [Google Scholar]
  59. Landrum M.J. Lee J.M. Benson M. ClinVar: Public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016 44 D1 D862 D868 10.1093/nar/gkv1222 26582918
    [Google Scholar]
  60. Koblan L.W. Doman J.L. Wilson C. Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction. Nat. Biotechnol. 2018 36 9 843 846 10.1038/nbt.4172 29813047
    [Google Scholar]
  61. Lee H.K. Oh Y. Hong J. Lee S.H. Hur J.K. Development of CRISPR technology for precise single-base genome editing: A brief review. BMB Rep. 2021 54 2 98 105 10.5483/BMBRep.2021.54.2.217 33298245
    [Google Scholar]
  62. Gaudelli N.M. Komor A.C. Rees H.A. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 2017 551 7681 464 471 10.1038/nature24644 29160308
    [Google Scholar]
  63. Richter M.F. Zhao K.T. Eton E. Phage-assisted evolution of an adenine base editor with improved Cas domain compatibility and activity. Nat. Biotechnol. 2020 38 7 883 891 10.1038/s41587‑020‑0453‑z 32433547
    [Google Scholar]
  64. Liang P. Huang J. Off-target challenge for base editor-mediated genome editing. Cell Biol. Toxicol. 2019 35 3 185 187 10.1007/s10565‑019‑09474‑8 31041571
    [Google Scholar]
  65. Lu C. Kuang J. Shao T. Prime editing: An all-rounder for genome editing. Int. J. Mol. Sci. 2022 23 17 9862 10.3390/ijms23179862 36077252
    [Google Scholar]
  66. Zhao D. Li J. Li S. Glycosylase base editors enable C-to-A and C-to-G base changes. Nat. Biotechnol. 2021 39 1 35 40 10.1038/s41587‑020‑0592‑2 32690970
    [Google Scholar]
  67. Sun N. Zhao D. Li S. Zhang Z. Bi C. Zhang X. Reconstructed glycosylase base editors GBE2.0 with enhanced C-to-G base editing efficiency and purity. Mol. Ther. 2022 30 7 2452 2463 10.1016/j.ymthe.2022.03.023 35381364
    [Google Scholar]
  68. Yang C. Dong X. Ma Z. Li B. Bi C. Zhang X. Pioneer factor improves crispr‐based C‐To‐G and C‐To‐T base editing. Adv. Sci. 2022 9 26 2202957 10.1002/advs.202202957 35861371
    [Google Scholar]
  69. Yeh W.H. Shubina-Oleinik O. Levy J.M. In vivo base editing restores sensory transduction and transiently improves auditory function in a mouse model of recessive deafness. Sci. Transl. Med. 2020 12 546 eaay9101 10.1126/scitranslmed.aay9101 32493795
    [Google Scholar]
  70. Koblan L.W. Erdos M.R. Wilson C. In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice. Nature 2021 589 7843 608 614 10.1038/s41586‑020‑03086‑7 33408413
    [Google Scholar]
  71. Ryu S.M. Koo T. Kim K. Adenine base editing in mouse embryos and an adult mouse model of Duchenne muscular dystrophy. Nat. Biotechnol. 2018 36 6 536 539 10.1038/nbt.4148 29702637
    [Google Scholar]
  72. Kurt I.C. Zhou R. Iyer S. CRISPR C-to-G base editors for inducing targeted DNA transversions in human cells. Nat. Biotechnol. 2021 39 1 41 46 10.1038/s41587‑020‑0609‑x 32690971
    [Google Scholar]
  73. Chen L. Park J.E. Paa P. Programmable C:G to G:C genome editing with CRISPR-Cas9-directed base excision repair proteins. Nat. Commun. 2021 12 1 1384 10.1038/s41467‑021‑21559‑9 33654077
    [Google Scholar]
  74. Scholefield J. Harrison P.T. Prime editing – An update on the field. Gene Ther. 2021 28 7-8 396 401 10.1038/s41434‑021‑00263‑9 34031549
    [Google Scholar]
  75. Anzalone A.V. Randolph P.B. Davis J.R. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 2019 576 7785 149 157 10.1038/s41586‑019‑1711‑4 31634902
    [Google Scholar]
  76. Liu Y. Li X. He S. Efficient generation of mouse models with the prime editing system. Cell Discov. 2020 6 1 27 10.1038/s41421‑020‑0165‑z 32351707
    [Google Scholar]
  77. Liang R. He Z. Zhao K.T. Prime editing using CRISPR-Cas12a and circular RNAs in human cells. Nat. Biotechnol. 2024 42 12 1867 1875 10.1038/s41587‑023‑02095‑x 38200119
    [Google Scholar]
  78. Yan J. Oyler-Castrillo P. Ravisankar P. Improving prime editing with an endogenous small RNA-binding protein. Nature 2024 628 8008 639 647 10.1038/s41586‑024‑07259‑6 38570691
    [Google Scholar]
  79. Abudayyeh O.O. Gootenberg J.S. Konermann S. C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. Science 2016 353 6299 aaf5573 10.1126/science.aaf5573 27256883
    [Google Scholar]
  80. Behr M. Zhou J. Xu B. Zhang H. In vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges. Acta Pharm. Sin. B 2021 11 8 2150 2171 10.1016/j.apsb.2021.05.020 34522582
    [Google Scholar]
  81. Smargon A.A. Cox D.B.T. Pyzocha N.K. Cas13b is a type VI-B CRISPR-associated RNA-guided rnase differentially regulated by accessory proteins Csx27 and Csx28. Mol. Cell 2017 65 4 618 630.e7 10.1016/j.molcel.2016.12.023 28065598
    [Google Scholar]
  82. Konermann S. Lotfy P. Brideau N.J. Oki J. Shokhirev M.N. Hsu P.D. Transcriptome engineering with RNA-targeting type VI-D CRISPR effectors. Cell 2018 173 3 665 676.e14 10.1016/j.cell.2018.02.033 29551272
    [Google Scholar]
  83. Kannan S. Altae-Tran H. Jin X. Compact RNA editors with small Cas13 proteins. Nat. Biotechnol. 2022 40 2 194 197 10.1038/s41587‑021‑01030‑2 34462587
    [Google Scholar]
  84. Xu C. Zhou Y. Xiao Q. Programmable RNA editing with compact CRISPR–Cas13 systems from uncultivated microbes. Nat. Methods 2021 18 5 499 506 10.1038/s41592‑021‑01124‑4 33941935
    [Google Scholar]
  85. Yan Z. Yao Y. Li L. Treatment of autosomal dominant retinitis pigmentosa caused by RHO-P23H mutation with high-fidelity Cas13X in mice. Mol. Ther. Nucleic Acids 2023 33 750 761 10.1016/j.omtn.2023.08.002 37621413
    [Google Scholar]
  86. Nishikura K. Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 2010 79 1 321 349 10.1146/annurev‑biochem‑060208‑105251 20192758
    [Google Scholar]
  87. Yi Z. Qu L. Tang H. Engineered circular ADAR-recruiting RNAs increase the efficiency and fidelity of RNA editing in vitro and in vivo. Nat. Biotechnol. 2022 40 6 946 955 10.1038/s41587‑021‑01180‑3 35145313
    [Google Scholar]
  88. Reautschnig P. Wahn N. Wettengel J. CLUSTER guide RNAs enable precise and efficient RNA editing with endogenous ADAR enzymes in vivo. Nat. Biotechnol. 2022 40 5 759 768 10.1038/s41587‑021‑01105‑0 34980913
    [Google Scholar]
  89. Katrekar D. Yen J. Xiang Y. Efficient in vitro and in vivo RNA editing via recruitment of endogenous ADARs using circular guide RNAs. Nat. Biotechnol. 2022 40 6 938 945 10.1038/s41587‑021‑01171‑4 35145312
    [Google Scholar]
  90. Monian P. Shivalila C. Lu G. Endogenous ADAR-mediated RNA editing in non-human primates using stereopure chemically modified oligonucleotides. Nat. Biotechnol. 2022 40 7 1093 1102 10.1038/s41587‑022‑01225‑1 35256816
    [Google Scholar]
  91. Baker A.R. Slack F.J. ADAR1 and its implications in cancer development and treatment. Trends Genet. 2022 38 8 821 830 10.1016/j.tig.2022.03.013 35459560
    [Google Scholar]
  92. Song J. Dong L. Sun H. CRISPR-free, programmable RNA pseudouridylation to suppress premature termination codons. Mol. Cell 2023 83 1 139 155.e9 10.1016/j.molcel.2022.11.011 36521489
    [Google Scholar]
  93. Zheng Z. Shi N. Xia Q. Adeno-associated viral delivery of engineered tRNA-enzyme pairs into nonsense mutation mouse models. STAR Protoc 2023 4 1 101950 10.1016/j.xpro.2022.101950 36527714
    [Google Scholar]
  94. Huang Q. Chan K.Y. Wu J. An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery. Science 2024 384 6701 1220 1227 10.1126/science.adm8386 38753766
    [Google Scholar]
  95. Dogbevia G. Grasshoff H. Othman A. Penno A. Schwaninger M. Brain endothelial specific gene therapy improves experimental Sandhoff disease. J. Cereb. Blood Flow Metab. 2020 40 6 1338 1350 10.1177/0271678X19865917 31357902
    [Google Scholar]
  96. Körbelin J. Dogbevia G. Michelfelder S. A brain microvasculature endothelial cell‐specific viral vector with the potential to treat neurovascular and neurological diseases. EMBO Mol. Med. 2016 8 6 609 625 10.15252/emmm.201506078 27137490
    [Google Scholar]
  97. Wu G. Liu S. Hagenstein J. Adeno-associated virus–based gene therapy treats inflammatory kidney disease in mice. J. Clin. Invest. 2024 134 17 174722 10.1172/JCI174722 39225099
    [Google Scholar]
  98. Mei W. Xiang G. Li Y. GDF11 protects against endothelial injury and reduces atherosclerotic lesion formation in apolipoprotein E-Null mice. Mol. Ther. 2016 24 11 1926 1938 10.1038/mt.2016.160 27502608
    [Google Scholar]
  99. He X. Wang X. Wang H. NeuroD1 regulated endothelial gene expression to modulate transduction of AAV-PHP.eB and recovery progress after ischemic stroke. Aging Dis. 2023 15 6 2632 2649 10.14336/AD.2023.1213 38270116
    [Google Scholar]
  100. Zhu W. Shen F. Mao L. Soluble FLT1 gene therapy alleviates brain arteriovenous malformation severity. Stroke 2017 48 5 1420 1423 10.1161/STROKEAHA.116.015713 28325846
    [Google Scholar]
  101. Ravindra Kumar S. Miles T.F. Chen X. Multiplexed Cre-dependent selection yields systemic AAVs for targeting distinct brain cell types. Nat. Methods 2020 17 5 541 550 10.1038/s41592‑020‑0799‑7 32313222
    [Google Scholar]
  102. Varadi K. Michelfelder S. Korff T. Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors. Gene Ther. 2012 19 8 800 809 10.1038/gt.2011.143 21956692
    [Google Scholar]
  103. Körbelin J. Sieber T. Michelfelder S. Pulmonary targeting of adeno-associated viral vectors by next-generation sequencing-guided screening of random capsid displayed peptide libraries. Mol. Ther. 2016 24 6 1050 1061 10.1038/mt.2016.62 27018516
    [Google Scholar]
  104. Periasamy R. Patel D.D. Boye S.L. Boye S.E. Lipinski D.M. Improving retinal vascular endothelial cell tropism through rational rAAV capsid design. PLoS One 2023 18 5 0285370 10.1371/journal.pone.0285370 37167304
    [Google Scholar]
  105. Barbon E. Kawecki C. Marmier S. Development of a dual hybrid AAV vector for endothelial-targeted expression of von Willebrand factor. Gene Ther. 2023 30 3-4 245 254 10.1038/s41434‑020‑00218‑6 33456057
    [Google Scholar]
  106. Wu W. Yang Y. Yao F. AAV-mediated in vivo genome editing in vascular endothelial cells. Methods 2021 194 12 17 10.1016/j.ymeth.2020.12.001 33309782
    [Google Scholar]
  107. Eriksson E. Moreno R. Milenova I. Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment. Gene Ther. 2017 24 2 92 103 10.1038/gt.2016.80 27906162
    [Google Scholar]
  108. Rossi C. Lees M. Mehta V. Comparison of efficiency and function of vascular endothelial growth factor adenovirus vectors in endothelial cells for gene therapy of placental insufficiency. Hum. Gene Ther. 2020 31 21-22 1190 1202 10.1089/hum.2020.006 32988220
    [Google Scholar]
  109. Tonetto E. Cucci A. Follenzi A. Bernardi F. Pinotti M. Balestra D. DNA base editing corrects common hemophilia A mutations and restores factor VIII expression in in vitro and ex vivo models. J. Thromb. Haemost. 2024 22 8 2171 2183 10.1016/j.jtha.2024.04.020 38718928
    [Google Scholar]
  110. Simmons A.B. Bretz C.A. Wang H. Gene therapy knockdown of VEGFR2 in retinal endothelial cells to treat retinopathy. Angiogenesis 2018 21 4 751 764 10.1007/s10456‑018‑9618‑5 29730824
    [Google Scholar]
  111. Milani M. Canepari C. Assanelli S. GP64-pseudotyped lentiviral vectors target liver endothelial cells and correct hemophilia A mice. EMBO Mol. Med. 2024 16 6 1427 1450 10.1038/s44321‑024‑00072‑8 38684862
    [Google Scholar]
  112. Merlin S. Cannizzo E.S. Borroni E. A novel platform for immune tolerance induction in hemophilia a mice. Mol. Ther. 2017 25 8 1815 1830 10.1016/j.ymthe.2017.04.029 28552407
    [Google Scholar]
  113. Ryu J.Y. Cerecedo-Lopez C. Yang H. Ryu I. Du R. Brain-targeted intranasal delivery of protein-based gene therapy for treatment of ischemic stroke. Theranostics 2024 14 12 4773 4786 10.7150/thno.98088 39239521
    [Google Scholar]
  114. Feng Y. Guo M. Liu W. Co-self-assembly of cationic microparticles to deliver pEGFP-ZNF580 for promoting the transfection and migration of endothelial cells. Int. J. Nanomedicine 2016 12 137 149 10.2147/IJN.S107593 28053529
    [Google Scholar]
  115. Hao X. Li Q. Lv J. CREDVW-linked polymeric micelles as a targeting gene transfer vector for selective transfection and proliferation of endothelial cells. ACS Appl. Mater. Interfaces 2015 7 22 12128 12140 10.1021/acsami.5b02399 26011845
    [Google Scholar]
  116. Zhang X. Jin H. Huang X. Robust genome editing in adult vascular endothelium by nanoparticle delivery of CRISPR-Cas9 plasmid DNA. Cell Rep. 2022 38 1 110196 10.1016/j.celrep.2021.110196 34986352
    [Google Scholar]
  117. Bozoglu T. Lee S. Ziegler T. Endothelial retargeting of AAV9 in vivo. Adv. Sci. 2022 9 7 2103867 10.1002/advs.202103867 35023328
    [Google Scholar]
  118. Tian S. Feng M. Cao D. Endothelial cell-targeted pVEGF165 polyplex plays a pivotal role in inhibiting intimal thickening after vascular injury. Int. J. Nanomedicine 2015 10 5751 5768 10.2147/IJN.S88109 26425083
    [Google Scholar]
/content/journals/cgt/10.2174/0115665232386151250812105845
Loading
Unraveling Etiological Indications and Therapeutic Implications of Familial Cerebral Cavernous Malformations in the Dawn of Gene Therapy for Monogenic Conditions
Bentham Science Publishers ; https://doi.org/10.2174/0115665232386151250812105845
/content/journals/cgt/10.2174/0115665232386151250812105845
/content/journals/cgt/10.2174/0115665232386151250812105845
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: gene therapy ; Cerebral cavernous malformations ; CRISPR Cas9 ; base editing ; Central nervous system ; monogenic disease

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test