Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gene-based therapies for neurodegenerative diseases

Abstract

Gene therapy is making a comeback. With its twin promise of targeting disease etiology and ‘long-term correction’, gene-based therapies (defined here as all forms of genome manipulation) are particularly appealing for neurodegenerative diseases, for which conventional pharmacologic approaches have been largely disappointing. The recent success of a viral-vector-based gene therapy in spinal muscular atrophy—promoting survival and motor function with a single intravenous injection—offers a paradigm for such therapeutic intervention and a platform to build on. Although challenges remain, the newfound optimism largely stems from advances in the development of viral vectors that can diffusely deliver genes throughout the CNS, as well as genome-engineering tools that can manipulate disease pathways in ways that were previously impossible. Surely spinal muscular atrophy cannot be the only neurodegenerative disease amenable to gene therapy, and one can imagine a future in which the toolkit of a clinician will include gene-based therapeutics. The goal of this Review is to highlight advances in the development and application of gene-based therapies for neurodegenerative diseases and offer a prospective look into this emerging arena.

Fig. 1: Timeline of marquee events in the gene-therapy field.
Fig. 2: Mechanisms of genome editing by engineered nucleases.
Fig. 3: Noncanonical CRISPR tools.
Fig. 4: Mechanisms of ASOs.
Fig. 5: ASO and CRISPR-based editing strategies to modulate APP cleavage products.

References

  1. 1.

    Somanathan, S., Calcedo, R. & Wilson, J. M. Adenovirus–antibody complexes contributed to lethal systemic inflammation in a gene therapy trial. Mol. Ther. 28, 784–793 (2020).

    CAS  PubMed  Google Scholar 

  2. 2.

    Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017).

    CAS  PubMed  Google Scholar 

  3. 3.

    Keeler, C. E. Gene therapy. J. Hered. 38, 294–298 (1947).

    CAS  PubMed  Google Scholar 

  4. 4.

    Logovinsky, V. et al. Safety and tolerability of BAN2401—a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res. Ther. 8, 14 (2016).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Hudry, E. & Vandenberghe, L. H. Therapeutic AAV gene transfer to the nervous system: a clinical reality. Neuron 102, 839–862 (2019).

    Google Scholar 

  6. 6.

    Doudna, J. A. The promise and challenge of therapeutic genome editing. Nature 578, 229–236 (2020).

    CAS  PubMed  Google Scholar 

  7. 7.

    Huang, L. K., Chao, S. P. & Hu, C. J. Clinical trials of new drugs for Alzheimer disease. J. Biomed. Sci. 27, 18 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bedbrook, C. N., Deverman, B. E. & Gradinaru, V. Viral strategies for targeting the central and peripheral nervous systems. Annu. Rev. Neurosci. https://doi.org/10.1146/annurev-neuro-080317-062048 (2018).

  9. 9.

    Leone, P. et al. Long-term follow-up after gene therapy for canavan disease. Sci. Transl Med. 4, 165ra163 (2012).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Ginn, S. L., Amaya, A. K., Alexander, I. E., Edelstein, M. & Abedi, M. R. Gene therapy clinical trials worldwide to 2017: an update. J. Gene Med. 20, e3015 (2018).

    PubMed  Google Scholar 

  11. 11.

    Calcedo, R., Vandenberghe, L. H., Gao, G., Lin, J. & Wilson, J. M. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J. Infect. Dis. 199, 381–390 (2009).

    PubMed  Google Scholar 

  12. 12.

    Mingozzi, F. et al. CD8+ T-cell responses to adeno-associated virus capsid in humans. Nat. Med. 13, 419–422 (2007).

    CAS  PubMed  Google Scholar 

  13. 13.

    Petry, H. et al. Effect of viral dose on neutralizing antibody response and transgene expression after AAV1 vector re-administration in mice. Gene Ther. 15, 54–60 (2008).

    CAS  PubMed  Google Scholar 

  14. 14.

    Lu, Y. & Song, S. Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors. Proc. Natl Acad. Sci. USA 106, 17158–17162 (2009).

    CAS  PubMed  Google Scholar 

  15. 15.

    Ashley, S. N., Somanathan, S., Giles, A. R. & Wilson, J. M. TLR9 signaling mediates adaptive immunity following systemic AAV gene therapy. Cell Immunol. 346, 103997 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Mendell, J. R. et al. Dystrophin immunity in Duchenne’s muscular dystrophy. N. Engl. J. Med. 363, 1429–1437 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wilson, J. M. & Flotte, T. R. Moving forward after two deaths in a gene therapy trial of myotubular myopathy. Hum. Gene Ther. 31, 695–696 (2020).

    CAS  PubMed  Google Scholar 

  18. 18.

    Hinderer, C. et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum. Gene Ther. 29, 285–298 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Nidetz, N. F. et al. Adeno-associated viral vector-mediated immune responses: understanding barriers to gene delivery. Pharmacol. Ther. 207, 107453 (2020).

    CAS  PubMed  Google Scholar 

  20. 20.

    Pickar-Oliver, A. & Gersbach, C. A. The next generation of CRISPR–Cas technologies and applications. Nat. Rev. Mol. Cell Biol. 20, 490–507 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Mullard, A. First in vivo CRISPR candidate enters the clinic. Nat. Rev. Drug Discov. 18, 656 (2019).

    PubMed  Google Scholar 

  22. 22.

    Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S. & Gregory, P. D. Genome editing with engineered zinc finger nucleases. Nat. Rev. Genet. 11, 636–646 (2010).

    CAS  PubMed  Google Scholar 

  23. 23.

    Joung, J. K. & Sander, J. D. TALENs: a widely applicable technology for targeted genome editing. Nat. Rev. Mol. Cell Biol. 14, 49–55 (2013).

    CAS  PubMed  Google Scholar 

  24. 24.

    Willems, J. et al. ORANGE: a CRISPR/Cas9-based genome editing toolbox for epitope tagging of endogenous proteins in neurons. PLoS Biol. 18, e3000665 (2020).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Park, S. H. et al. Highly efficient editing of the β-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease. Nucleic Acids Res. 47, 7955–7972 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Sugaya, K. & Vaidya, M. Stem cell therapies for neurodegenerative diseases. Adv. Exp. Med. Biol. 1056, 61–84 (2018).

    CAS  PubMed  Google Scholar 

  27. 27.

    Maeder, M. L. et al. Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nat. Med. 25, 229–233 (2019).

    CAS  PubMed  Google Scholar 

  28. 28.

    Sun, J. et al. CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage. Nat. Commun. 10, 53 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Popp, M. W. & Maquat, L. E. Leveraging rules of nonsense-mediated mRNA decay for genome engineering and personalized medicine. Cell 165, 1319–1322 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Lau, C. H., Ho, J. W., Lo, P. K. & Tin, C. Targeted transgene activation in the brain tissue by systemic delivery of engineered AAV1 expressing CRISPRa. Mol. Ther. Nucleic Acids 16, 637–649 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Landrum, M. J. et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 42, D980–D985 (2014).

    CAS  PubMed  Google Scholar 

  32. 32.

    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 533, 420–424 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Gaudelli, N. M. et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kim, Y. B. et al. Increasing the genome-targeting scope and precision of base editing with engineered Cas9–cytidine deaminase fusions. Nat. Biotechnol. 35, 371–376 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Levy, J. M. et al. Cytosine and adenine base editing of the brain, liver, retina, heart and skeletal muscle of mice via adeno-associated viruses. Nat. Biomed. Eng. 4, 97–110 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Grunewald, J. et al. Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors. Nature 569, 433–437 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Zuo, E. et al. A rationally engineered cytosine base editor retains high on-target activity while reducing both DNA and RNA off-target effects. Nat. Methods 17, 600–604 (2020).

    CAS  PubMed  Google Scholar 

  38. 38.

    Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Rinaldi, C. & Wood, M. J. A. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat. Rev. Neurol. 14, 9–21 (2018).

    CAS  PubMed  Google Scholar 

  40. 40.

    Leavitt, B. R. & Tabrizi, S. J. Antisense oligonucleotides for neurodegeneration. Science 367, 1428–1429 (2020).

    CAS  PubMed  Google Scholar 

  41. 41.

    Chen, G., Katrekar, D. & Mali, P. RNA-guided adenosine deaminases: advances and challenges for therapeutic RNA editing. Biochemistry 58, 1947–1957 (2019).

    CAS  PubMed  Google Scholar 

  42. 42.

    Abudayyeh, O. O. et al. RNA targeting with CRISPR–Cas13. Nature 550, 280–284 (2017).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Konermann, S. et al. Transcriptome engineering with RNA-targeting type VI-D CRISPR effectors. Cell 173, 665–676.e14 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Abudayyeh, O. O. et al. A cytosine deaminase for programmable single-base RNA editing. Science 365, 382–386 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).

    CAS  PubMed  Google Scholar 

  46. 46.

    Han, K. J. et al. Ubiquitin-specific protease 9× deubiquitinates and stabilizes the spinal muscular atrophy protein-survival motor neuron. J. Biol. Chem. 287, 43741–43752 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Passini, M. A. et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci. Transl Med. 3, 72ra18 (2011).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Darras, B. T. et al. Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies. Neurology 92, e2492–e2506 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017).

    CAS  PubMed  Google Scholar 

  50. 50.

    Finkel, R. S. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388, 3017–3026 (2016).

    CAS  PubMed  Google Scholar 

  51. 51.

    Naryshkin, N. A. et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345, 688–693 (2014).

    CAS  PubMed  Google Scholar 

  52. 52.

    Zhou, M. et al. Seamless genetic conversion of SMN2 to SMN1 via CRISPR/Cpf1 and single-stranded oligodeoxynucleotides in spinal muscular atrophy patient-specific induced pluripotent stem cells. Hum. Gene Ther. 29, 1252–1263 (2018).

    CAS  PubMed  Google Scholar 

  53. 53.

    Al-Zaidy, S. et al. Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr. Pulmonol. 54, 179–185 (2019).

    PubMed  Google Scholar 

  54. 54.

    Sun, J. & Roy, S. The physical approximation of APP and BACE-1: a key event in Alzheimer’s disease pathogenesis. Dev. Neurobiol. 78, 340–347 (2018).

    CAS  PubMed  Google Scholar 

  55. 55.

    Das, U. et al. Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nat. Neurosci. 19, 55–64 (2016).

    CAS  PubMed  Google Scholar 

  56. 56.

    Huang, Y. A., Zhou, B., Wernig, M. & Sudhof, T. C. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell 168, 427–441.e21 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Doran, E. et al. Down syndrome, partial trisomy 21, and absence of Alzheimer’s disease: the role of APP. J. Alzheimers Dis. 56, 459–470 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Li, C. & Gotz, J. Tau-based therapies in neurodegeneration: opportunities and challenges. Nat. Rev. Drug Discov. 16, 863–883 (2017).

    CAS  PubMed  Google Scholar 

  59. 59.

    Tuszynski, M. H. et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat. Med. 11, 551–555 (2005).

    CAS  PubMed  Google Scholar 

  60. 60.

    Nagahara, A. H. et al. Long-term reversal of cholinergic neuronal decline in aged non-human primates by lentiviral NGF gene delivery. Exp. Neurol. 215, 153–159 (2009).

    CAS  PubMed  Google Scholar 

  61. 61.

    Rafii, M. S. et al. Adeno-associated viral vector (serotype 2)-nerve growth factor for patients with Alzheimer disease: a randomized clinical trial. JAMA Neurol. 75, 834–841 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Castle, M. J. et al. Postmortem analysis in a clinical trial of AAV2–NGF gene therapy for Alzheimer’s disease identifies a need for improved vector delivery. Hum. Gene Ther. 31, 415–422 (2020).

    CAS  PubMed  Google Scholar 

  63. 63.

    Nagahara, A. H. et al. MR-guided delivery of AAV2–BDNF into the entorhinal cortex of non-human primates. Gene Ther. 25, 104–114 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    DeVos, S. L. et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aag0481 (2017).

  65. 65.

    Sud, R., Geller, E. T. & Schellenberg, G. D. Antisense-mediated exon skipping decreases tau protein expression: a potential therapy for tauopathies. Mol. Ther. Nucleic Acids 3, e180 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Velazquez, R. et al. Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits. Aging Cell https://doi.org/10.1111/acel.12775 (2018).

  67. 67.

    Zhou, L. et al. Tau association with synaptic vesicles causes presynaptic dysfunction. Nat. Commun. 8, 15295 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Yu, J. T., Tan, L. & Hardy, J. Apolipoprotein E in Alzheimer’s disease: an update. Annu. Rev. Neurosci. 37, 79–100 (2014).

    CAS  PubMed  Google Scholar 

  69. 69.

    Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501–518 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Hudry, E. et al. Gene transfer of human APOE isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci. Transl Med. 5, 212ra161 (2013).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Rosenberg, J. B. et al. AAVrh.10-mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer’s disease. Hum. Gene Ther. Clin. Dev. 29, 24–47 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Lin, Y.-T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Gyorgy, B. et al. CRISPR/Cas9 mediated disruption of the Swedish APP allele as a therapeutic approach for early-onset Alzheimer’s disease. Mol. Ther. Nucleic Acids 11, 429–440 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Chang, J. L. et al. Targeting amyloid-β precursor protein, APP, splicing with antisense oligonucleotides reduces toxic amyloid-β production. Mol. Ther. 26, 1539–1551 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Muller, U. C., Deller, T. & Korte, M. Not just amyloid: physiological functions of the amyloid precursor protein family. Nat. Rev. Neurosci. 18, 281–298 (2017).

    PubMed  Google Scholar 

  76. 76.

    Iyer, S. et al. Precise therapeutic gene correction by a simple nuclease-induced double-stranded break. Nature 568, 561–565 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Fol, R. et al. Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model. Acta Neuropathol. 131, 247–266 (2016).

    CAS  PubMed  Google Scholar 

  78. 78.

    Obeso, J. A. et al. Functional organization of the basal ganglia: therapeutic implications for Parkinson’s disease. Mov. Disord. 23, S548–S559 (2008).

    PubMed  Google Scholar 

  79. 79.

    Christine, C. W. et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73, 1662–1669 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Mittermeyer, G. et al. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson’s disease. Hum. Gene Ther. 23, 377–381 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    San Sebastian, W. et al. Safety and tolerability of magnetic resonance imaging-guided convection-enhanced delivery of AAV2–hAADC with a novel delivery platform in nonhuman primate striatum. Hum. Gene Ther. 23, 210–217 (2012).

    CAS  PubMed  Google Scholar 

  82. 82.

    Palfi, S. et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet 383, 1138–1146 (2014).

    CAS  Google Scholar 

  83. 83.

    Baron, M. S., Wichmann, T., Ma, D. & DeLong, M. R. Effects of transient focal inactivation of the basal ganglia in parkinsonian primates. J. Neurosci. 22, 592–599 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Emborg, M. E. et al. Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism. J. Cereb. Blood Flow. Metab. 27, 501–509 (2007).

    CAS  PubMed  Google Scholar 

  85. 85.

    Luo, J. et al. Subthalamic GAD gene therapy in a Parkinson’s disease rat model. Science 298, 425–429 (2002).

    CAS  PubMed  Google Scholar 

  86. 86.

    Kaplitt, M. G. et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet 369, 2097–2105 (2007).

    CAS  PubMed  Google Scholar 

  87. 87.

    LeWitt, P. A. et al. AAV2–GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 10, 309–319 (2011).

    CAS  Google Scholar 

  88. 88.

    Niethammer, M. et al. Long-term follow-up of a randomized AAV2–GAD gene therapy trial for Parkinson’s disease. JCI Insight 2, e90133 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Collier, T. J. & Sortwell, C. E. Therapeutic potential of nerve growth factors in Parkinson’s disease. Drugs Aging 14, 261–287 (1999).

    CAS  PubMed  Google Scholar 

  90. 90.

    Chen, Y. H. et al. MPTP-induced deficits in striatal synaptic plasticity are prevented by glial cell line-derived neurotrophic factor expressed via an adeno-associated viral vector. FASEB J. 22, 261–275 (2008).

    CAS  PubMed  Google Scholar 

  91. 91.

    Su, X. et al. Safety evaluation of AAV2–GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Hum. Gene Ther. 20, 1627–1640 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Marks, W. J. Jr. et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I trial. Lancet Neurol. 7, 400–408 (2008).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Marks, W. J. Jr et al. Gene delivery of AAV2–neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 9, 1164–1172 (2010).

    CAS  PubMed  Google Scholar 

  94. 94.

    Bartus, R. T. et al. Bioactivity of AAV2–neurturin gene therapy (CERE-120): differences between Parkinson’s disease and nonhuman primate brains. Mov. Disord. 26, 27–36 (2011).

    PubMed  Google Scholar 

  95. 95.

    Bartus, R. T. et al. Safety/feasibility of targeting the substantia nigra with AAV2–neurturin in Parkinson patients. Neurology 80, 1698–1701 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Decressac, M. et al. α-synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Sci. Transl Med. 4, 163ra156 (2012).

    PubMed  Google Scholar 

  97. 97.

    Qian, H. et al. Reversing a model of Parkinson’s disease with in situ converted nigral neurons. Nature 582, 550–556 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Wong, Y. C. & Krainc, D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat. Med. 23, 1–13 (2017).

    CAS  PubMed  Google Scholar 

  99. 99.

    Soldner, F. et al. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature 533, 95–99 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Fuchs, J. et al. Genetic variability in the SNCA gene influences α-synuclein levels in the blood and brain. FASEB J. 22, 1327–1334 (2008).

    CAS  PubMed  Google Scholar 

  101. 101.

    Zharikov, A. D. et al. shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model. J. Clin. Invest. 125, 2721–2735 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Uehara, T. et al. Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson’s disease. Sci. Rep. 9, 7567 (2019).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Kantor, B. et al. Downregulation of SNCA expression by targeted editing of DNA methylation: a potential strategy for precision therapy in PD. Mol. Ther. 26, 2638–2649 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Benskey, M. J. et al. Silencing alpha synuclein in mature nigral neurons results in rapid neuroinflammation and subsequent toxicity. Front. Mol. Neurosci. 11, 36 (2018).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Gorbatyuk, O. S. et al. In vivo RNAi-mediated α-synuclein silencing induces nigrostriatal degeneration. Mol. Ther. 18, 1450–1457 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Sidransky, E. et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 361, 1651–1661 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Do, J., McKinney, C., Sharma, P. & Sidransky, E. Glucocerebrosidase and its relevance to Parkinson disease. Mol. Neurodegener. 14, 36 (2019).

    PubMed  PubMed Central  Google Scholar 

  108. 108.

    Sardi, S. P. et al. Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies. Proc. Natl Acad. Sci. USA 110, 3537–3542 (2013).

    CAS  PubMed  Google Scholar 

  109. 109.

    Morabito, G. et al. AAV-PHP.B-mediated global-scale expression in the mouse nervous system enables GBA1 gene therapy for wide protection from synucleinopathy. Mol. Ther. 25, 2727–2742 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Gandhi, P. N., Chen, S. G. & Wilson-Delfosse, A. L. Leucine-rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of Parkinson’s disease. J. Neurosci. Res. 87, 1283–1295 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Hatcher, J. M., Choi, H. G., Alessi, D. R. & Gray, N. S. Small-molecule inhibitors of LRRK2. Adv. Neurobiol. 14, 241–264 (2017).

    PubMed  Google Scholar 

  112. 112.

    Ness, D. et al. Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLoS ONE 8, e66164 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Fuji, R. N. et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci. Transl Med. 7, 273ra215 (2015).

    Google Scholar 

  114. 114.

    Baptista, M. A. et al. Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. PLoS ONE 8, e80705 (2013).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Zhao, H. T. et al. LRRK2 antisense oligonucleotides ameliorate α-synuclein inclusion formation in a Parkinson’s disease mouse model. Mol. Ther. Nucleic Acids 8, 508–519 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Ross, C. A. & Tabrizi, S. J. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 10, 83–98 (2011).

    CAS  PubMed  Google Scholar 

  117. 117.

    Kordasiewicz, H. B. et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74, 1031–1044 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Tabrizi, S. J. et al. Targeting huntingtin expression in patients with Huntington’s disease. N. Engl. J. Med. 380, 2307–2316 (2019).

    CAS  PubMed  Google Scholar 

  119. 119.

    Rodrigues, F. B., Ferreira, J. J. & Wild, E. J. Huntington’s disease clinical trials corner: June 2019. J. Huntingtons Dis. 8, 363–371 (2019).

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Evers, M. M. et al. AAV5–miHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a Huntington’s disease minipig model. Mol. Ther. 26, 2163–2177 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Boudreau, R. L. et al. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Mol. Ther. 17, 1053–1063 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Stanek, L. M. et al. Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington’s disease. Hum. Gene Ther. 25, 461–474 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    McBride, J. L. et al. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol. Ther. 19, 2152–2162 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Grondin, R. et al. Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 135, 1197–1209 (2012).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Wang, G., Liu, X., Gaertig, M. A., Li, S. & Li, X. J. Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis. Proc. Natl Acad. Sci. USA 113, 3359–3364 (2016).

    CAS  Google Scholar 

  126. 126.

    Dietrich, P., Johnson, I. M., Alli, S. & Dragatsis, I. Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis. PLoS Genet. 13, e1006846 (2017).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Shin, J. W. et al. Permanent inactivation of Huntington’s disease mutation by personalized allele-specific CRISPR/Cas9. Hum. Mol. Genet. 25, 4566–4576 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    van Bilsen, P. H. et al. Identification and allele-specific silencing of the mutant huntingtin allele in Huntington’s disease patient-derived fibroblasts. Hum. Gene Ther. 19, 710–719 (2008).

    PubMed  Google Scholar 

  129. 129.

    Southwell, A. L. et al. In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides. Mol. Ther. 22, 2093–2106 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Pfister, E. L. et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr. Biol. 19, 774–778 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Rodrigues, F. B. & Wild, E. J. Huntington’s disease clinical trials corner: February 2018. J. Huntingtons Dis. 7, 89–98 (2018).

    PubMed  PubMed Central  Google Scholar 

  132. 132.

    Zeitler, B. et al. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat. Med. 25, 1131–1142 (2019).

    CAS  PubMed  Google Scholar 

  133. 133.

    Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R. & Gitler, A. D. ALS genetics: gains, losses, and implications for future therapies. Neuron https://doi.org/10.1016/j.neuron.2020.08.022 (2020).

  134. 134.

    Bruijn, L. I. et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281, 1851–1854 (1998).

    CAS  PubMed  Google Scholar 

  135. 135.

    Smith, R. A. et al. Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Invest. 116, 2290–2296 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 12, 435–442 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Miller, T. et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 383, 109–119 (2020).

    CAS  PubMed  Google Scholar 

  138. 138.

    Foust, K. D. et al. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol. Ther. 21, 2148–2159 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Gaj, T. et al. In vivo genome editing improves motor function and extends survival in a mouse model of ALS. Sci. Adv. 3, eaar3952 (2017).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Mueller, C. et al. SOD1 suppression with adeno-associated virus and microRNA in familial ALS. N. Engl. J. Med. 383, 151–158 (2020).

    CAS  PubMed  Google Scholar 

  141. 141.

    DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Haeusler, A. R., Donnelly, C. J. & Rothstein, J. D. The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nat. Rev. Neurosci. 17, 383–395 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Jiang, J. et al. Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron 90, 535–550 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Tuszynski, M. H. et al. Nerve growth factor gene therapy: activation of neuronal responses in Alzheimer disease. JAMA Neurol. 72, 1139–1147 (2015).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Christine, C. W. et al. Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease. Ann. Neurol. 85, 704–714 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    McFarthing, K., Prakash, N. & Simuni, T. Clinical trial highlights: 1. Gene therapy for Parkinson’s, 2. Phase 3 study in focus—INTEC Pharma’s accordion pill, 3. Clinical trials resources. J. Parkinsons Dis. 9, 251–264 (2019).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Darras, B. T. et al. An integrated safety analysis of infants and children with symptomatic spinal muscular atrophy (SMA) treated with nusinersen in seven clinical trials. CNS Drugs 33, 919–932 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Mercuri, E. et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N. Engl. J. Med. 378, 625–635 (2018).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank L. Parra, B. Aulston, D. Galasko, and J. Brewer (all at UCSD) for comments on the manuscript. The authors apologize that due to space restrictions, primary papers could not be cited in most cases. Work in the Sun Lab is supported by NSFC grants 82071193 and 32000673. Work in the Roy Lab is supported by grants from the NIH (R01AG048218, R01NS11978, R01NS075233, R21AG052404 and UG3NS111688) and the US–Israel Binational Science Foundation (BSF, number 2019248).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Subhojit Roy.

Ethics declarations

Competing interests

J.S. and S.R. have applied for patents related to gene editing in AD (US patent application number 16251970). S.R. is also the scientific founder of, advisor to, and owns equity in CRISPRAlz.

Additional information

Peer review information Nature Neuroscience thanks the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sun, J., Roy, S. Gene-based therapies for neurodegenerative diseases. Nat Neurosci 24, 297–311 (2021). https://doi.org/10.1038/s41593-020-00778-1

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing