Therapeutic Potential of Conjugated siRNAs for the Treatment of Major Depressive Disorder

Major depressive disorder (MDD) is a severe psychiatric syndrome with very-high socioeconomic impact worldwide (Global Burden of Disease Study 2013 Collaborators, 2015). This is attributable to three main factors: (i) MDD is a highly prevalent disorder in the general population, (ii) depressive episodes have long duration and occur during active periods of adult life, resulting in very large labor costs, and (iii) standard MDD treatments have limited efficacy, leaving a high percentage of patients with incomplete responses and poor quality of life, thus increasing suicide risk (Rush et al, 2006).Peer reviewe

RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis

Open Access: This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.-- et al.Current antidepressants, which inhibit the serotonin transporter (SERT), display limited efficacy and slow onset of action. Here, we show that partial reduction of SERT expression by small interference RNA (SERT-siRNA) decreased immobility in the tail suspension test, displaying an antidepressant potential. Moreover, short-term SERT-siRNA treatment modified mouse brain variables considered to be key markers of antidepressant action: reduced expression and function of 5-HT(1A)-autoreceptors, elevated extracellular serotonin in forebrain and increased neurogenesis and expression of plasticity-related genes (BDNF, VEGF, Arc) in hippocampus. Remarkably, these effects occurred much earlier and were of greater magnitude than those evoked by long-term fluoxetine treatment. These findings highlight the critical role of SERT in serotonergic function and show that the reduction of SERT expression regulates serotonergic neurotransmission more potently than pharmacological blockade of SERT. The use of siRNA-targeting genes in serotonin neurons (SERT, 5-HT(1A)-autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants.This research was supported by grants from Spanish Ministry of Science and Innovation-CDTI, with the participation of the DENDRIA Consortium; from Instituto de Salud Carlos III PI10/00290 and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM, P91C). Structural funds of the European Union, through the National Applied Research Projects (R+D+I 2008/11) and from the Catalan Government (grant 2009SGR220) are also acknowledged.Peer Reviewe

Oligonucleotide therapies for disorders of the nervous system

Oligonucleotide therapies are currently experiencing a resurgence driven by advances in backbone chemistry and discoveries of novel therapeutic pathways that can be uniquely and efficiently modulated by the oligonucleotide drugs. A quarter of a century has passed since oligonucleotides were first applied in living mammalian brain to modulate gene expression. Despite challenges in delivery to the brain, multiple oligonucleotide-based compounds are now being developed for treatment of human brain disorders by direct delivery inside the blood brain barrier (BBB). Notably, the first new central nervous system (CNS)-targeted oligonucleotide-based drug (nusinersen/Spinraza) was approved by US Food and Drug Administration (FDA) in late 2016 and several other compounds are in advanced clinical trials. Human testing of brain-targeted oligonucleotides has highlighted unusual pharmacokinetic and pharmacodynamic properties of these compounds, including complex active uptake mechanisms, low systemic exposure, extremely long half-lives, accumulation and gradual release from subcellular depots. Further work on oligonucleotide uptake, development of formulations for delivery across the BBB and relevant disease biology studies are required for further optimization of the oligonucleotide drug development process for brain applications