Ten years after Fire and Melo's Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2-3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development.

No abstract

The present review examines whether the microRNA 7 (miR-7) holds potential for slowing Parkinson's disease (PD) progression. First, the accurate expression of miR-7 allows for normal development, physiology, and neurogenesis in the central nervous system, also keeping alpha-synuclein (α-Syn) at the physiological level. Second, patients with PD and parkinsonian MPTP-induced animals exhibit a significant decrease of miR-7 in brain areas associated with dopaminergic neurodegeneration. Depletion of miR-7 in the substantia nigra of clinical samples is related to α-Syn accumulation, loss of dopaminergic cells, and reduction of dopamine in the striatum. Therefore, the goal of a miR-7- replacement therapy is to downregulate α-Syn and other PD-related genes, achieving multi-target benefits regarding oxidative stress, mitochondrial health, cell glycolysis, apoptosis, and inhibition of inflammasome activation. While a disease-modifying drug is a major unmet need for the clinical management of PD, an miR-7-replacement therapy presents a striking potential against critical mechanisms of neuropathology. Such innovative treatment would reduce α-Syn accumulation in the Lewy bodies and preserve remaining neurons yet viable at the time of diagnosis, thus slowing disease progression from the early phase of PD characterized by a relatively mild motor impairment to an advanced and more disabling stage.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections lead to acute- and chronic Long COVID (LC) symptoms. However, few studies have addressed LC sequelae on brain functions. This study was aimed to examine if acute symptoms of coronavirus disease 2019 (COVID-19) would persist during LC, and if memory problems would be correlated with sleep, depressive mood, or anxious complaints. Methods Our work followed a cohort of 236 patients from two public hospitals of the Federal District in mid-western Brazil. Patients’ interviews checked for clinical symptoms during acute and LC (5–8 months after real-time reverse transcription polymerase chain reaction, RT-qPCR). Results Most cases were non-hospitalized individuals (86.3%) with a median age of 41.2 years. While myalgia (50%), hyposmia (48.3%), and dysgeusia (45.8%) were prevalent symptoms in acute phase, fatigue (21.6%) followed by headache (19.1%) and myalgia (16.1%) commonly occurred during LC. In LC, 39.8% of individuals reported memory complaints, 36.9% felt anxious, 44.9% felt depressed, and 45.8% had sleep problems. Furthermore, memory complaints were associated with sleep problems (adjusted OR 3.206; 95% CI 1.723–6.030) and depressive feelings (adjusted OR 3.981; 95% CI 2.068–7.815). Conclusions The SARS-CoV-2 infection leads to persistent symptoms during LC, in which memory problems may be associated with sleep and depressive complaints.

Glioblastoma multiforme (GBM) is the most aggressive type of human primary brain tumor. The standard treatment protocol includes radiotherapy in combination with temozolomide (TMZ). Despite advances in GBM treatment, the survival time of patients diagnosed with glioma is 14.5 months. Regarding tumor biology, various types of cancer cell overexpress the ether à go-go 1 (Eag1) potassium channel. Therefore, the present study examined the role of Eag1 in the cell damage caused by TMZ on the U87MG glioblastoma cell line. Eag1 was inhibited using a channel blocker (astemizole) or silenced by a short-hairpin RNA expression vector (pKv10.1-3). pKv10.1-3 (0.2 µg) improved the Eag1 silencing caused by 250 µM TMZ, as determined by reverse transcription-quantitative polymerase chain reaction and immunocytochemistry. Additionally, inhibiting Eag1 with the vector or astemizole (5 µM) reduced glioblastoma cell viability and sensitized cells to TMZ. Cell viability decreased by 63% for pKv10.1-3 + TMZ compared with 34% for TMZ alone, and by 77% for astemizole + TMZ compared with 46% for TMZ alone, as determined by MTT assay. In addition, both the vector and astemizole increased the apoptosis rate of glioblastoma cells triggered by TMZ, as determined by an Annexin V apoptosis assay. Collectively, the current data reveal that Eag1 has a role in the damage caused to glioblastoma by TMZ. Furthermore, suppression of this channel can improve the action of TMZ on U87MG glioblastoma cells. Thus, silencing Eag1 is a promising strategy to improve GBM treatment and merits additional studies in animal models of glioma.

MicroRNAs (miRNAs) are small double-stranded RNAs that exert a fine-tuning sequence-specific regulation of cell transcriptome. While one unique miRNA regulates hundreds of mRNAs, each mRNA molecule is commonly regulated by various miRNAs that bind to complementary sequences at 3’-untranslated regions for triggering the mechanism of RNA interference. Unfortunately, dysregulated miRNAs play critical roles in many disorders, including Parkinson’s disease (PD), the second most prevalent neurodegenerative disease in the world. Treatment of this slowly, progressive, and yet incurable pathology challenges neurologists. In addition to L-DOPA that restores dopaminergic transmission and ameliorate motor signs (i.e., bradykinesia, rigidity, tremors), patients commonly receive medication for mood disorders and autonomic dysfunctions. However, the effectiveness of L-DOPA declines over time, and the L-DOPA-induced dyskinesias commonly appear and become highly disabling. The discovery of more effective therapies capable of slowing disease progression –a neuroprotective agent–remains a critical need in PD. The present review focus on miRNAs as promising drug targets for PD, examining their role in underlying mechanisms of the disease, the strategies for controlling aberrant expressions, and, finally, the current technologies for translating these small molecules from bench to clinics.

No abstract

No abstract