PMID- 33915178
OWN - NLM
STAT- MEDLINE
DCOM- 20220120
LR  - 20220120
IS  - 1879-016X (Electronic)
IS  - 0163-7258 (Linking)
VI  - 227
DP  - 2021 Nov
TI  - Oligonucleotides as therapeutic tools for brain disorders: Focus on major 
      depressive disorder and Parkinson's disease.
PG  - 107873
LID - S0163-7258(21)00075-9 [pii]
LID - 10.1016/j.pharmthera.2021.107873 [doi]
AB  - 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.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Bortolozzi, Analia
AU  - Bortolozzi A
AD  - Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de 
      Investigaciones Cientificas (CSIC), 08036 Barcelona, Spain; Institut 
      d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de 
      Investigacion Biomedica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain. 
      Electronic address: analia.bortolozzi@iibb.csic.es.
FAU - Manashirov, Sharon
AU  - Manashirov S
AD  - Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), ISCIII, 
      Madrid, Spain; miCure Therapeutics LTD., Tel-Aviv, Israel; Department of Stress 
      Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, 
      Germany.
FAU - Chen, Alon
AU  - Chen A
AD  - Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of 
      Psychiatry, 80804 Munich, Germany; Department of Neurobiology, Weizmann Institute 
      of Science, 76100 Rehovot, Israel.
FAU - Artigas, Francesc
AU  - Artigas F
AD  - Institut d'Investigacions Biomediques de Barcelona (IIBB), Consejo Superior de 
      Investigaciones Cientificas (CSIC), 08036 Barcelona, Spain; Institut 
      d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de 
      Investigacion Biomedica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20210427
PL  - England
TA  - Pharmacol Ther
JT  - Pharmacology & therapeutics
JID - 7905840
RN  - 0 (Oligonucleotides)
SB  - IM
MH  - *Depressive Disorder, Major/drug therapy
MH  - Humans
MH  - *Oligonucleotides/therapeutic use
MH  - *Parkinson Disease/drug therapy
OTO - NOTNLM
OT  - ASO
OT  - Brain delivery
OT  - Depression
OT  - Oligonucleotide therapeutics
OT  - Parkinson's disease
OT  - miRNA
EDAT- 2021/04/30 06:00
MHDA- 2022/01/21 06:00
CRDT- 2021/04/29 20:13
PHST- 2020/11/18 00:00 [received]
PHST- 2021/04/05 00:00 [accepted]
PHST- 2021/04/30 06:00 [pubmed]
PHST- 2022/01/21 06:00 [medline]
PHST- 2021/04/29 20:13 [entrez]
AID - S0163-7258(21)00075-9 [pii]
AID - 10.1016/j.pharmthera.2021.107873 [doi]
PST - ppublish
SO  - Pharmacol Ther. 2021 Nov;227:107873. doi: 10.1016/j.pharmthera.2021.107873. Epub 
      2021 Apr 27.