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Oligonucleotides as therapeutic tools for brain disorders: Focus on major depressive disorder and Parkinson’s disease.
Abstract
Remarkable advances in understanding the role of RNA in health and disease have expanded considerably in the last decade. RNA is becoming an increasingly important target for therapeutic intervention; therefore, it is critical to develop strategies for therapeutic modulation of RNA function. Oligonucleotides, including antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA mimic (miRNA), and anti-microRNA (antagomir) are perhaps the most direct therapeutic strategies for addressing RNA. Among other mechanisms, most oligonucleotide designs involve the formation of a hybrid with RNA that promotes its degradation by activation of endogenous enzymes such as RNase-H (e.g., ASO) or the RISC complex (e.g. RNA interference - RNAi for siRNA and miRNA). However, the use of oligonucleotides for the treatment of brain disorders is seriously compromised by two main limitations: i) how to deliver oligonucleotides to the brain compartment, avoiding the action of peripheral RNAses? and once there, ii) how to target specific neuronal populations? We review the main molecular pathways in major depressive disorder (MDD) and Parkinson's disease (PD), and discuss the challenges associated with the development of novel oligonucleotide therapeutics. We pay special attention to the use of conjugated ligand-oligonucleotide approach in which the oligonucleotide sequence is covalently bound to monoamine transporter inhibitors (e.g. sertraline, reboxetine, indatraline). This strategy allows their selective accumulation in the monoamine neurons of mice and monkeys after their intranasal or intracerebroventricular administration, evoking preclinical changes predictive of a clinical therapeutic action after knocking-down disease-related genes. In addition, recent advances in oligonucleotide therapeutic clinical trials are also reviewed.
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“In MMD, it has been reported that miRNAs are not only involved in the pathogenesis of the disease [17], but are also associated with depression caused by various illnesses [18, 19], as well as the response to specific treatments such as isoliquiritin [20], oligonucleotides [21], or purinergic receptor [22], confirming their potential as disease monitoring biomarkers.”
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Wu, Z., Cai, Z., Shi, H., Huang, X., Cai, M., Yuan, K., Huang, P., Shi, G., Yan, T., & Li, Z. (2022) · Aging · doi:10.18632/aging.204030 · Cited by 37
Metadata
- Authors
- Bortolozzi, A., Manashirov, S., Chen, A., & Artigas, F.
- Affiliations
- Instituto de Salud Carlos III (ES)
- Max Planck Institute of Psychiatry (DE)
- Consejo Superior de Investigaciones Científicas (ES)
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 227
- Pages
- 107873
- ISSN
- 0163-7258 (ISSN-L)
- OpenAlex
- W3159813053
- Cited by
- 37
- References
- 345
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 9 · 2023: 9 · 2022: 9
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Centro de Investigación Biomédica en Red de Salud Mental
- European Regional Development Fund
- Government of Spain Ministry of Economy and Competitiveness
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- oligonucleotide therapeutics, antisense oligonucleotides, siRNA, miRNA mimics, antagomir, RNA interference, major depressive disorder, Parkinson's disease, brain disorders, sertraline, reboxetine, monoaminergic neurons, RNase H, RNA-induced silencing complex, intranasal administration, intracerebroventricular administration, gene knockdown
- MeSH terms
- Depressive Disorder, Major, Major Depressive Disorder, Humans, Oligonucleotides, Parkinson Disease
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