Neurodegenerative diseases as a target for genome editing: from preclinical studies to clinical practice

封面
  • 作者: Tereshchenko S.Y.1, Potupchik T.V.2, Evert L.S.1,3, Alieva L.G.4, Kozyrina Y.E.5, Maremkulov A.A.5
  • 隶属关系:
    1. Federal Research Center “Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences” – Separate Subdivision Scientific Research Institute of Medical Problems of the North
    2. Federal State Budgetary Educational Institution of Higher Education “Krasnoyarsk State Medical University named after Professor V.F. Voino-Yasenetsky” of the Ministry of Health of the Russian Federation
    3. Khakass State University named after N.F. Katanov of the Ministry of Science and Higher Education of the Russian Federation
    4. Federal State Autonomous Educational Institution of Higher Education “Peoples’ Friendship University of Russia named after Patrice Lumumba”, Ministry of Science and Higher Education of the Russian Federation
    5. Federal State Autonomous Educational Institution of Higher Education “N.I. Pirogov Russian National Research Medical University” of the Ministry of Health of the Russian Federation
  • 期: 卷 23, 编号 1 (2025)
  • 页面: 16-26
  • 栏目: Reviews
  • URL: https://journals.eco-vector.com/1728-2918/article/view/689290
  • DOI: https://doi.org/10.29296/24999490-2025-01-02
  • ID: 689290

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详细

Objective. To analyze the current state of preclinical and clinical studies in genome editing for neurodegenerative diseases, evaluate its potential impact on clinical practice, and examine ethical aspects of these technologies’ application.

Material and methods. A systematic literature review was conducted for the period 2016-2024 using PubMed, Cochrane Library, ClinicalTrials.gov, SAGE Premier, Springer, and Wiley Journals databases, using key words: “genome editing”, “CRISPR”, “neurodegenerative diseases”, “clinical trials”, “ethics”.

Results. Key genetic targets for genome editing in Alzheimer’s disease (APP, PSEN1/2, APOE), Parkinson’s disease (LRRK2, PARK7, SNCA), and Huntington’s disease (HTT) are examined. Results of key preclinical studies demonstrating the effectiveness of various genome editing approaches are analyzed. The success of initial clinical trials of genome editing technologies in related fields and their significance for developing neurodegenerative disease therapies are discussed. Ethical aspects of genome editing application in the nervous system are considered.

Conclusion. Despite significant progress in preclinical studies, the transition to clinical application of genome editing technologies in neurodegenerative diseases requires addressing multiple technical, biological, and ethical challenges. Success in clinical trials in related fields provides a foundation for developing effective therapeutic strategies.

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作者简介

Sergey Tereshchenko

Federal Research Center “Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences” – Separate Subdivision Scientific Research Institute of Medical Problems of the North

编辑信件的主要联系方式.
Email: legise@mail.ru
ORCID iD: 0000-0002-1605-7859

Head of the Clinical Department of Somatic and Mental Health of Children, Doctor of Medical Sciences, Professor

俄罗斯联邦, Partizan Zheleznyak str., 3G, Krasnoyarsk, 660022

Tatyana Potupchik

Federal State Budgetary Educational Institution of Higher Education “Krasnoyarsk State Medical University named after Professor V.F. Voino-Yasenetsky” of the Ministry of Health of the Russian Federation

Email: potupchik_tatyana@mail.ru
ORCID iD: 0000-0003-1133-4447

Associate Professor, Department of Pharmacology and Clinical Pharmacology with a Postgraduate Course, Candidate of Medical Sciences

俄罗斯联邦, Partizan Zheleznyak str., 1, Krasnoyarsk, 660022

Lydia Evert

Federal Research Center “Krasnoyarsk Scientific Center of the Siberian Branch of the Russian Academy of Sciences” – Separate Subdivision Scientific Research Institute of Medical Problems of the North; Khakass State University named after N.F. Katanov of the Ministry of Science and Higher Education of the Russian Federation

Email: lidiya_evert@mail.ru
ORCID iD: 0000-0003-0665-7428

Chief Researcher, Clinical Department of Somatic and Mental Health of Children, Professor, Department of General Professional Disciplines, Medical Institute, Doctor of Medical Sciences

俄罗斯联邦, Partizan Zheleznyak str., 3G, Krasnoyarsk, 660022; Lenin Ave., 90, Abakan, 655017

Leila Alieva

Federal State Autonomous Educational Institution of Higher Education “Peoples’ Friendship University of Russia named after Patrice Lumumba”, Ministry of Science and Higher Education of the Russian Federation

Email: alievaoxx@mail.ru
ORCID iD: 0009-0006-2500-9687

6th year student

俄罗斯联邦, Miklukho-Maklaya str., 6, Moscow, 117198

Yuliana Kozyrina

Federal State Autonomous Educational Institution of Higher Education “N.I. Pirogov Russian National Research Medical University” of the Ministry of Health of the Russian Federation

Email: iuliana.kozyrina@mail.ru
ORCID iD: 0009-0003-9023-1936

6th year student

俄罗斯联邦, Ostrovityanova str., 1, Moscow, 117513

Amin Maremkulov

Federal State Autonomous Educational Institution of Higher Education “N.I. Pirogov Russian National Research Medical University” of the Ministry of Health of the Russian Federation

Email: headshoter1985@mail.ru
ORCID iD: 0009-0009-3505-5523

6th year student

俄罗斯联邦, Ostrovityanova str., 1, Moscow, 117513

参考

  1. Cerçi B., Uzay I.A., Kara M.K., Dinçer P. Clinical trials and promising preclinical applications of CRISPR/Cas gene editing. Life Sci. 2023; 312: 121204. doi: 10.1016/j.lfs.2022.121204
  2. Lu L., Yu X., Cai Y., Sun M., Yang H. Application of CRISPR/Cas9 in Alzheimer’s Disease. Frontiers in Neuroscience. 2021; 15: 803894. doi: 10.3389/fnins.2021.803894
  3. Györgyi B., Lööv C., Zaborowski M.P., Takeda S., Kleinstiver B.P., Commins C., Kastanenka K. et al. CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer’s Disease. Molecular Therapy – Nucleic Acids. 2018; 11: 429–40. doi: 10.1016/j.omtn.2018.03.007
  4. Kwart D., Gregg A., Scheckel C., Murphy E.A., Paquet D., Tessier-Lavigne M., J. Fak et al. A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP b-CTFs, Not Ab. Neuron. 2019; 104: 256–70. doi: 10.1016/j.neuron.2019.07.010
  5. Luo J., Li Y.-M. Turning the tide on Alzheimer’s disease: modulation of γ-secretase. Cell & Bioscience. 2022; 12 (2). doi: 10.1186/s13578-021-00738-7
  6. Zhao J., Fu Y., Yamazaki Y., Ren Y., Davis M.D., Liu C.-C., Lu W. et al. APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids. Nature Communications. 2021; 12 (1): 2707. doi: 10.1038/s41467-021-23081-4
  7. Lin Y.-T., Seo J., Gao F., Feldman H.M., Wen H.-L., Penney J., Cam H.P et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018; 98 (6): 1294–312.e7. doi: 10.1016/j.neuron.2018.05.008
  8. Song W., Hooli B., Mullin K., Jin S.C., Cella M., Ulland T.K., Wang Y. et al. Alzheimer’s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 2017; 13 (4): 381–7. doi: 10.1016/j.jalz.2016.08.011
  9. Gratuze M., Leyns C.E.G., Holtzman D.M. New insights into the role of TREM2 in Alzheimer’s disease. Molecular Neurodegeneration. 2018; 13 (1): 66. doi: 10.1186/s13024-018-0298-9
  10. De Rossi P., Buggia-Prévot V., Clayton B.L.L., Vasquez J.B., van Sanford C., Andrew R.J., Pytel P. et al. BIN1 localization is distinct from Tau tangles in Alzheimer’s disease. Matters. 2017. doi: 10.19185/matters.201611000018
  11. Wolinetz C.D, Collins F.S. NIH supports call for moratorium on clinical uses of germline gene editing. Nature. 2019; 567 (7747): 175. doi: 10.1038/d41586-019-00814-6.
  12. Kalia L.V., Lang A.E. Parkinson’s disease. Lancet. 2015; 386 (9996): 896–912. doi: 10.1016/S0140-6736(14)61393-3.
  13. Tappakhov A., Popova T.E., Nikolaeva T.Ya., Gurieva P.I., Shnayder N.A., Petrova M.M., Sapronova M.R. Genetic Basis of Parkinson’s Disease. Neurology neuropsychiatry Psychosomatics. 2017; 9 (1): 96–100. doi: 10.14412/2074-2711-2017-1-96-100
  14. Qing X., Walter J., Jarazo J., Arias-Fuenzalida J., Hillje A.-L., Schwamborn J.C. CRISPR/Cas9 and piggyBac-mediated footprint-free LRRK2-G2019S knock-in reveals neuronal complexity phenotypes and α-Synuclein modulation in dopaminergic neurons. Stem Cell Research. 2017; 24: 44–50. doi: 10.1016/j.scr.2017.08.013.
  15. Heman-Ackah S.M., Bassett A.R., Wood M.J. Precision Modulation of Neurodegenerative Disease-Related Gene Expression in Human iPSC-Derived Neurons. Sci Rep. 2016; 6: 28420. doi: 10.1038/srep28420.
  16. 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): 420–4. doi: 10.1038/nature17946
  17. Wetzel A., Lei S.H., Liu T., Hughes M.P. , Peng Y. , McKay T., Waddington S.N. et al. Dysregulated Wnt and NFAT signaling in a Parkinson’s disease LRRK2 G2019S knock-in model. Sci Rep. 2024; 14 (1): 12393. doi: 10.1038/s41598-024-63130-8.
  18. Repici M., Giorgini F. DJ-1 in Parkinson’s Disease: Clinical Insights and Therapeutic Perspectives. J. of Clinical Medicine. 2019; 8 (9): 1377. doi: 10.3390/jcm8091377
  19. Meade R.M., Fairlie D.P., Mason, J.M. Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles. Mol Neurodegeneration. 2019; 14: 29. doi: 10.1186/s13024-019-0329-1
  20. Soldner F., Stelzer Y., Shivalila C.S., Abraham B.J., Latourelle J.C., Barrasa M.I., Goldmann J. et al. Parkinson-Associated Risk Variant in Distal Enhancer of α-Synuclein Modulates Target Gene Expression. Nature. 2016; 533 (7601): 95–9. doi: 10.1038/nature17939
  21. Chung S.Y., Kishinevsky S., Mazzulli J.R. , Graziotto J. , Mrejeru A., Mosharov E.V., Puspita L. et al. Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation Stem Cell Reports. 2016; 7 (4): 664–77. doi: 10.1016/j.stemcr.2016.08.012.
  22. Chin R.M., Rakhit R., Ditsworth D., Wang C., Bartholomeus J., Liu S., Mody A. et al. Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models. bioRxiv [Preprint]. 2023: 2023.02.14.528378. doi: 10.1101/2023.02.14.528378.
  23. Zunke F., Mazzulli J.R. Modeling neuronopathic storage diseases with patient-derived culture systems. Neurobiol Dis. 2019; 127: 147–62. doi: 10.1016/j.nbd.2019.01.018.
  24. McColgan P., Tabrizi S.J. Huntington’s disease: a clinical review. European J. of Neurology. 2018; 25 (1): 24–34. doi: 10.1111/ene.13413
  25. Shin J.W., Kim K.H., Chao M.J., Atwal R.S., Gillis T., MacDonald M.E., Gusella J.F. et al. Permanent inactivation of Huntington’s disease mutation by personalized allele-specific CRISPR/Cas9. Human Molecular Genetics. 2016; 25 (20): 4566–76. doi: 10.1093/hmg/ddw286
  26. Monteys A.M., Ebanks S.A., Keiser M.S., Davidson B.L. CRISPR/Cas9 editing of the mutant huntingtin allele in vitro and in vivo. Molecular Therapy. 2017; 25 (1): 12–23. doi: 10.1016/j.ymthe.2016.10.012
  27. Fink K.D. , Deng P., Gutierrez J., Anderson J.S., Torrest A., Komarla A., Kalomoiris S. et al. Allele-Specific Reduction of the Mutant Huntingtin Allele Using Transcription Activator-Like Effectors in Human Huntington’s Disease Fibroblasts Cell Transplant. 2016; 25 (4): 677–86. doi: 10.3727/096368916X690863.
  28. Yang S., Chang R., Yang H., Zhao T., Hong Y., Kong H.E., Sun X. et al. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. J. of Clinical Investigation. 2017; 127 (7): 2719–24. doi: 10.1172/JCI92087
  29. Laundos T.L., Li S., Cheang E., De Santis R., Piccolo F.M., Brivanlou A.H. Huntingtin CAG-expansion mutation results in a dominant negative effect. Cell Dev. Biol. 2023;11. doi: 10.3389/fcell.2023.1252521
  30. Nicole D., Vachey G., Rey M., Perrier A. Allele specific gene editing for huntington’s disease mediated by the KAMICAS9 self-inactivating CRISPR/CAS9 system. J. of Neurology, Neurosurgery and Psychiatry. 2018; 89 (1): A90.2–A90. doi: 10.1136/jnnp-2018-EHDN.243
  31. Massey T., Jones L.The central role of DNA damage and repair in CAG repeat diseases. Disease Models and Mechanisms. 2018; 11 (1): dmm031930. doi: 10.1242/dmm.031930
  32. Dabrowska M., Juzwa W., Krzyzosiak W.J., Olejniczak M. Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases. Front. Neurosci. 2018; 12: 75. doi: 10.3389/fnins.2018.00075
  33. Grigor’eva E.V., Kopytova A.E., Yarkova E.S., Pavlova S.V., Sorogina D.A., Malakhova A.A., Malankhanova T.B. et al. Biochemical Characteristics of iPSC-Derived Dopaminergic Neurons from N370S GBA Variant Carriers with and without Parkinson’s Disease. Int. J. Mol. Sci. 2023; 24 (5): 4437. doi: 10.3390/ijms24054437
  34. Qu J., Liu N., Gao L., Hu J., Sun M., Yu D. Development of CRISPR Cas9, spin-off technologies and their application in model construction and potential therapeutic methods of Parkinson’s disease. Front. Neurosci. 2023; 17: 1223747. doi: 10.3389/fnins.2023.1223747
  35. Малахова А.А., Сорокин М.А., Сорокина А.Е., Маланханова Т.Б., Мазурок Н.А., Медведев С.П., Закиян С.М. Использование методов редактирования генома для создания изогенных клеточных линий, моделирующих болезнь Хантингтона in vitro Гены и клетки. 2016; 11 (2): 106–13. [Malakhova A.A., Sorokin M.A., Sorokina A.E., Malankhanova T.B., Mazurok N.A., Medvedev S.P., Zakiyan S.M. Using genome editing methods to create isogenic cell lines simulating Huntington’s disease in vitro Genes and cells. 2016; 11 (2): 106–13. (In Russian)].
  36. Shi Y., Zhao Y., Lu L., Gao Q., Yu D., Sun M. CRISPR/Cas9: implication for modeling and therapy of amyotrophic lateral sclerosis Front. Neurosci. 2023; 17: 1223777. doi: 10.3389/FNINS.2023.1223777
  37. Vertex Pharmaceuticals Incorporated, CRISPR Therapeutics. A safety and efficacy study evaluating CTX001 in subjects with transfusion-dependent p-thalassemia. National Institutes of Health. 2019.
  38. Vertex Pharmaceuticals Incorporated, CRISPR Therapeutics. A safety and efficacy study evaluating CTX001 in subjects with severe sickle cell disease. National Institutes of Health. 2019.
  39. Han Y., Tan X., Jin T., Zhao S., Hu L., Zhang W., Kurita R. et al. CRISPR/Cas9-based multiplex genome editing of BCL11A and HBG efficiently induces fetal hemoglobin expression Eur. J. Pharmacol. 2022; 918: 174788. doi: 10.1016/j.ejphar.2022.174788.
  40. Evaluation of Efficacy and Safety of a Single Dose of Exa-cel in Participants With Severe Sickle Cell Disease, βS/βC GenotypeUS Clinical Trials Registry. Clinical Trial NCT05951205.
  41. Allergan plc and Editas Medicine, Inc. Allergan and Editas Medicine Initiate the Brilliance Phase 1/2 Clinical Trial of AGN-151587 (EDIT-101) for the Treatment of LCA10. National Institutes of Health. 2019.
  42. Cheng S.-Y., Punzo C. Update on Viral Gene Therapy Clinical Trials for Retinal Diseases. Human Gene Therapy. 2022; 33: 865–78. doi: 10.1089/HUM.2022.159
  43. The VERVE-101 study in patients with familial hypercholesterolemia and cardiovascular diseases Registry of Clinical Trials in the USA. Clinical Trial NCT053980295. April 2024. updated: Verve Therapeutics, Inc. URL: https://ichgcp.net/ru/clinical-trials-registry/NCT05398029.
  44. Wang R., Ficiciolu C.Н., Giugliani R., Burke J. RGX-111 gene therapy for the treatment of severe mucopolysaccharidosis type I (MPS I): Interim analysis of data from the first in human study. Molecular Genetics and Metabolism. 2023; 138 (2): 107354. doi: 10.1016/j.ymgme.2022.107354
  45. Marks W.J., Baumann T.L., Bartus R.T. Long-Term Safety of Patients with Parkinson’s Disease Receiving rAAV2-Neurturin (CERE-120) Gene Transfer. Human Gene Therapy. 2016; 27 (7): 522–7. doi: 10.1089/hum.2015.134
  46. Frangoul H., Altshuler D., Cappellini M.D., Chen Y.S., Domm J., Eustace B.K., Foell J. et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. New England Journal of Medicine. 2021; 384 (3): 252–60. doi: 10.1056/NEJMoa2031054
  47. Gillmore J.D., Gane E., Taubel J., Kao J., Fontana M., Maitland M.L., Seitzer J. et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. New England J. of Medicine. 2021; 385: 493–502. doi: 10.1056/NEJMoa2107454
  48. Dunbar C.E., High K.A., Joung J.K., Kohn D.B., Ozawa K., Sadelain M. Gene therapy comes of age. Science. 2018; 359 (6372): eaan4672. doi: 10.1126/science.aan4672
  49. Baltimore D., Berg P., Botchan M., Carroll D., Charo R.A., Church G., Corn J.E. et al. Biotechnology. A prudent path forward for genomic engineering and germline gene modification. Science. 2015; 348 (6230): 36–8. doi: 10.1126/science.aab1028
  50. Howard H.C., van El C.G., Forzano F., Radojkovic D., Rial-Sebbag E., de Wert G., Borry P. et al. Public and Professional Policy Committee of the European Society of Human Genetics. One small edit for humans, one giant edit for humankind? Points and questions to consider for a responsible way forward for gene editing in humans. Eur. J. Hum Genet. 2018; 26 (1): 1–11. doi: 10.1038/s41431-017-0024-z.
  51. Ormond K.E., Mortlock D.P., Scholes D.T., Bombard Y., Brody L.C., Faucett W.A., Garrison N.A. et al. Human Germline Genome Editing. Am J Hum Genet. 2017; 101 (2): 167–76. doi: 10.1016/j.ajhg.2017.06.012.
  52. Cyranoski D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature. 2019; 566 (7745): 440–2. doi: 10.1038/d41586-019-00673-1

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