Skip to main content
SpringerLink
Log in

Antisense-Therapie neurologischer Erkrankungen

Antisense therapies for neurological diseases

  • Leitthema
  • Published:
Der Nervenarzt Aims and scope Submit manuscript

Zusammenfassung

In den letzten Jahrzehnten sind viele Gene neurodegenerativer Krankheiten kloniert worden. Trotzdem wurden Therapien dafür nur langsam entwickelt. Der vielleicht bedeutendste Vorteil der „antisense oligonucleotide therapeutics“, der sog. ASO-Therapeutika, gegenüber anderen Ansätzen besteht darin, dass die Kenntnis der Genzielsequenz unmittelbar Wissen über mögliche Komplementär-Oligonukleotid-Therapeutika vermittelt. In dieser Übersichtsarbeit beschreiben wir die verschiedenen Arten von ASOs, ihre therapeutische Verwendung und die derzeitigen präklinischen Bemühungen zur Entwicklung neuer ASO-Therapien.

Abstract

Despite identification of many genes causing neurodegenerative diseases in the last decades, development of disease-modifying treatments has been slow. Antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy, Duchenne muscular dystrophy and transthyretin amyloidosis predict a robust future for ASOs in medicine. Perhaps the most significant advantage of ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of possible complementary oligonucleotide therapeutics. This review article describes the various types of ASOs, their therapeutic use and the current preclinical efforts to develop new ASO treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Literatur

  1. Alarcón-Arís D, Recasens A, Galofre M et al (2018) Selective alpha-Synuclein knockdown in Monoamine neurons by Intranasal Oligonucleotide delivery: potential therapy for parkinson’s disease. Mol Ther 26(2):550–567

    Article  CAS  PubMed  Google Scholar 

  2. Becker LA, Huang B, Bieri G et al (2017) Therapeutic reduction of ataxin-2 extend lifespan and reduces pathology inTD-43 mice. Nature 544(7650):367–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bennet CF (2019) Therapeutic Antisense Oligonucleotides are coming of age. Annu Rev Med 70:307–321

    Article  CAS  Google Scholar 

  4. Benson MD, Waddington-Cruz M, Berk JL et al (2018) Inotersen treatment for patients with hereditary Transthyretin Amyloidosis. N Engl J Med 379(1):22–31

    Article  CAS  PubMed  Google Scholar 

  5. Chang JL, Hinrich AJ, Roman B et al (2018) Targeting Amyloid-beta precursor protein, APP, splicing with Antisense Oligonucleotides reduces toxic Amyloid-beta production. Mol Ther 26(6):1539–1551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Crooke ST, Wang S, Vickers TA et al (2017) Cellular uptake and trafficking of antisense oligonucleotides. Nat Biotechnol 35(3):230–237

    Article  CAS  PubMed  Google Scholar 

  7. Crooke ST, Baker BF, Xia S et al (2019) Integrated assessment of the clinical performance of GalNac3-conjugated 2′-O-Methoxyethyl chimeric Antisense Oligonucleotides: I. Human volunteer experience. Nucleic Acid Ther 29(1):16–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dansithong W, Paul S, Figueroa KP et al (2015) Ataxin-2 regulates RGS8 translation in a new BAC-SCA2 transgenic mouse model. Plos Genet 11(4):e1005182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. DeVos SL, Miller RL, Schoch KM et al (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 9(374):eaag481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. De Vivo DC, Hwu W‑L, Reyna SP et al (2017) Interim efficacy and safety results from the phase 2 Nurture study evaluating Nusinersen in presympotmatic infants with spinal muscular atrophy. Baillieres Clin Neurol 88(16 Suppl):46.003

    Google Scholar 

  11. Finkel RS, Mercuri E, Darras BT et al (2017) Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 377(18):1723–1732

    Article  CAS  PubMed  Google Scholar 

  12. Hansen ST, Meera P, Otis TS, Pulst SM (2013) Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet 22(2):271–283

    Article  CAS  PubMed  Google Scholar 

  13. Hinrich AJ, Jodelka FM, Chang JL et al (2016) Therapeutic correction of ApoER2 splicing in Alzheimer’s disease mice using antisense oligonucleotides. Embo Mol Med 8(4):328–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Iwamoto N, Butler DCD, Svrzikapa N et al (2017) Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat Biotechnol 35(9):845–851

    Article  CAS  PubMed  Google Scholar 

  15. Jiang J, Zhu Q, Gendron TF et al (2016) Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by Antisense Oligonucleotides targeting GGGGCC-containing RNas. Neuron 90(30):535–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lane RM, Smith A, Baumann T et al (2018) Translating Antisense technology into a treatment for Huntington’s disease. Methods Mol Biol 1780:497–523

    Article  CAS  PubMed  Google Scholar 

  17. Lim KR, Maruyama R, Yokota T (2017) Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther 11:533–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Marwick C (1998) First “antisense” drug will treat CMV retinitis. JAMA 280(10):871

    Article  CAS  PubMed  Google Scholar 

  19. McCampbell A, Cole T, Wegener AJ et al (2018) Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest 128(8):3558–3567

    Article  PubMed  PubMed Central  Google Scholar 

  20. McLoughlin HS, Moore LR, Chopra R et al (2018) Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann Neurol 84(1):64–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mercuri E, Darras BT, Chiriboga CA et al (2018) Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 378(7):625–635

    Article  CAS  PubMed  Google Scholar 

  22. Michelson D, Ciafaloni E, Ashwal S et al (2018) Evidence in focus: Nusinersen use in spinal muscular atrophy. Baillieres Clin Neurol 91(20):923–933

    Google Scholar 

  23. Neuenschwander AG, Thai KK, Figueroa KP et al (2014) Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis. Jama Neurol 71(12):1529–1534

    Article  PubMed  PubMed Central  Google Scholar 

  24. Niu C, Prakash TP, Kim A et al (2018) Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med 10(465):eaap8677

    Article  CAS  PubMed  Google Scholar 

  25. Oldenburg D, Guberina N, Stolte B et al (2019) Radiation exposure of image-guided intrathecal administration of nusinersen to adult patients with spinal muscular atrophy. Neuroradiology 61(5):565–574. https://doi.org/10.1007/s00234-019-02189-x

    Article  CAS  PubMed  Google Scholar 

  26. Scoles DR, Meera P, Schneider MD et al (2017) Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 554(7650):362–366

    Article  CAS  Google Scholar 

  27. Scoles DR, Minikel EV, Pulst SM (2019) Antisense oligonucleotides: a primer. Neurol Genet 5:e323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Toonen LJA, Rigo F, van Attikum H et al (2017) Antisense Oligonucleotide-mediated removal of the Polyglutamine repeat in spinocerebellar ataxia type 3 mice. Mol Ther Nucleic Acids 8:232–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhao HT, John N, Delic V et al (2017) LRRK2 Antisense Oligonucleotides ameliorate alpha-Synuclein inclusion formation in a parkinson’s disease mouse model. Mol Ther Nucleic Acids 8:508–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Danksagung

Diese Arbeit wurde unterstützt durch Forschungsvorhaben R21NS081182, R37NS033123 und U01NS103883 der National Institutes of Health (USA). Der Autor dankt cand. med. T.J. Pulst und Dr. Maria C. Wolpers für kritisches Lesen des Manuskriptes.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Utah, CNC Building, 5th Floor, 175 N Medical Drive E, 84132, Salt Lake City, UT, USA

    Stefan‑M. Pulst

Authors
  1. Stefan‑M. Pulst
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefan‑M. Pulst.

Ethics declarations

Interessenkonflikt

S.‑M. Pulst erhält Lizenzgebühren von der University of Utah, Cedars-Sinai Medical Center, und von der American Academy of Neurology. Er ist Mitbesitzer eines Patentes für ATXN2 ASOs mit Ionis Pharmaceuticals. Er ist Mitbegründer von Progenitor Lifesciences.

Für diesen Beitrag wurden vom Autor keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pulst, S. Antisense-Therapie neurologischer Erkrankungen. Nervenarzt 90, 781–786 (2019). https://doi.org/10.1007/s00115-019-0724-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00115-019-0724-4

Schlüsselwörter

Keywords

Search

Navigation