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Review
. 2023 Jan;40(1):77-105.
doi: 10.1007/s11095-022-03433-5. Epub 2022 Nov 15.

CNS Delivery of Nucleic Acid Therapeutics: Beyond the Blood-Brain Barrier and Towards Specific Cellular Targeting

Anisha D'Souza  1   2 , Saeideh Nozohouri  1 , Benjamin S Bleier  2 , Mansoor M Amiji  3   4
Affiliations
Review

CNS Delivery of Nucleic Acid Therapeutics: Beyond the Blood-Brain Barrier and Towards Specific Cellular Targeting

Anisha D'Souza et al. Pharm Res. 2023 Jan.

Abstract

Nucleic acid-based therapeutic molecules including small interfering RNA (siRNA), microRNA(miRNA), antisense oligonucleotides (ASOs), messenger RNA (mRNA), and DNA-based gene therapy have tremendous potential for treating diseases in the central nervous system (CNS). However, achieving clinically meaningful delivery to the brain and particularly to target cells and sub-cellular compartments is typically very challenging. Mediating cell-specific delivery in the CNS would be a crucial advance that mitigates off-target effects and toxicities. In this review, we describe these challenges and provide contemporary evidence of advances in cellular and sub-cellular delivery using a variety of delivery mechanisms and alternative routes of administration, including the nose-to-brain approach. Strategies to achieve subcellular localization, endosomal escape, cytosolic bioavailability, and nuclear transfer are also discussed. Ultimately, there are still many challenges to translating these experimental strategies into effective and clinically viable approaches for treating patients.

Keywords: CNS delivery; blood–brain barrier; cell-specificity; nucleic acid therapeutics.

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References

    1. Simonato M, Bennett J, Boulis NM, Castro MG, Fink DJ, Goins WF, et al. Progress in gene therapy for neurological disorders. Nat Rev Neurol. 2013;9(5):277–91. - DOI - PubMed - PMC
    1. Lima Giacobbo B, Doorduin J, Klein HC, Dierckx R, Bromberg E, de Vries EFJ. Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation. Mol Neurobiol. 2019;56(5):3295–312. - DOI - PubMed
    1. Nagabhushan Kalburgi S, Khan NN, Gray SJ. Recent gene therapy advancements for neurological diseases. Discov Med. 2013;15(81):111–9. - PubMed
    1. Piguet F, Alves S, Cartier N. Clinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and Future. Hum Gene Ther. 2017;28(11):988–1003. - DOI - PubMed
    1. Cicalese MP, Aiuti A. New perspectives in gene therapy for inherited disorders. Pediatr Allergy Immunol. 2020;31(Suppl 24):5–7. - DOI - PubMed

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