Skip to main content
PMC home page
Medline Book to support NIHPA logoLink to Medline Book to support NIHPA
. 2022;2434:345–353. doi: 10.1007/978-1-0716-2010-6_24

Intrathecal Delivery of Therapeutic Oligonucleotides for Potent Modulation of Gene Expression in the Central Nervous System.

Zachary Kennedy, James W Gilbert, Bruno M D C Godinho
PMCID: PMC9703256  PMID: 35213030

Abstract

Therapeutic oligonucleotides hold tremendous potential for treating central nervous system (CNS) disorders. The route of administration of oligonucleotides significantly impacts both distribution and silencing efficiency. Here, we describe a technically simple, clinically relevant method to administer oligonucleotide compounds into the CNS via direct intrathecal injections. This method achieves distribution throughout the CNS rapidly and permits high-throughput testing of oligonucleotide efficacy and potency in mammals.

Full text of this article can be found in Bookshelf.

References

  1. Relizani K, Goyenvalle A (2018) Use of Tricyclo-DNA antisense oligonucleotides for exon skipping. Methods Mol Biol 1828:381–394. https://doi.org/10.1007/978-1-4939-8651-4_24 doi: 10.1007/978-1-4939-8651-4_24. [DOI] [PubMed]
  2. Godinho B, Henninger N, Bouley J, Alterman JF, Haraszti RA, Gilbert JW, Sapp E, Coles AH, Biscans A, Nikan M, Echeverria D, DiFiglia M, Aronin N, Khvorova A (2018) Transvascular delivery of hydrophobically modified siRNAs: gene silencing in the rat brain upon disruption of the blood-brain barrier. Mol Ther 26(11):2580–2591. https://doi.org/10.1016/j.ymthe.2018.08.005 doi: 10.1016/j.ymthe.2018.08.005. [DOI] [PMC free article] [PubMed]
  3. Boursereau R, Donadieu A, Dabertrand F, Dubayle D, Morel JL (2015) Blood brain barrier precludes the cerebral arteries to intravenously-injected antisense oligonucleotide. Eur J Pharmacol 747:141–149. https://doi.org/10.1016/j.ejphar.2014.11.027 doi: 10.1016/j.ejphar.2014.11.027. [DOI] [PubMed]
  4. Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K, Ostrow LW, Schoenfeld D, Macklin EA, Norris DA, Manousakis G, Crisp M, Smith R, Bennett CF, Bishop KM, Cudkowicz ME (2013) 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(5):435–442. https://doi.org/10.1016/S1474-4422(13)70061-9 doi: 10.1016/S1474-4422(13)70061-9. [DOI] [PMC free article] [PubMed]
  5. Njoo C, Heinl C, Kuner R (2014) In vivo SiRNA transfection and gene knockdown in spinal cord via rapid noninvasive lumbar intrathecal injections in mice. J Vis Exp (85):51229. https://doi.org/10.3791/51229 doi: 10.3791/51229. [DOI] [PMC free article] [PubMed]
  6. Chen Y, Mazur C, Luo Y, Sun L, Zhang M, McCampbell A, Tomassy GS (2019) Intrathecal delivery of antisense oligonucleotides in the rat central nervous system. J Vis Exp (152). https://doi.org/10.3791/60274 doi: 10.3791/60274. [DOI] [PubMed]
  7. Hylden JL, Wilcox GL (1980) Intrathecal morphine in mice: a new technique. Eur J Pharmacol 67(2–3):313–316. https://doi.org/10.1016/0014-2999(80)90515-4 doi: 10.1016/0014-2999(80)90515-4. [DOI] [PubMed]
  8. Corey DR (2017) Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nat Neurosci 20(4):497–499. https://doi.org/10.1038/nn.4508 doi: 10.1038/nn.4508. [DOI] [PubMed]
  9. Guo Y, Wang D, Qiao T, Yang C, Su Q, Gao G, Xu Z (2016) A single injection of recombinant adeno-associated virus into the lumbar cistern delivers transgene expression throughout the whole spinal cord. Mol Neurobiol 53(5):3235–3248. https://doi.org/10.1007/s12035-015-9223-1 doi: 10.1007/s12035-015-9223-1. [DOI] [PMC free article] [PubMed]

RESOURCES