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Pharmacological Reviews Oct 2020RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various...
RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
Topics: Aptamers, Nucleotide; Betacoronavirus; COVID-19; Chemistry Techniques, Analytical; Clustered Regularly Interspaced Short Palindromic Repeats; Coronavirus Infections; Drug Delivery Systems; Drug Development; Drug Discovery; Humans; MicroRNAs; Oligonucleotides, Antisense; Pandemics; Pneumonia, Viral; RNA; RNA, Antisense; RNA, Messenger; RNA, Ribosomal; RNA, Small Interfering; RNA, Viral; Ribonucleases; Riboswitch; SARS-CoV-2
PubMed: 32929000
DOI: 10.1124/pr.120.019554 -
Journal of Clinical Laboratory Analysis Jul 2022The incidence of premature atherosclerotic cardiovascular disease in familial hypercholesterolemia (FH) is high. In recent years, novel therapeutic modalities have shown... (Review)
Review
BACKGROUND
The incidence of premature atherosclerotic cardiovascular disease in familial hypercholesterolemia (FH) is high. In recent years, novel therapeutic modalities have shown significant lipid-lowering ability. In this paper, we summarize the recent developments in novel therapies for FH via the treatment of different targets and discuss the characteristics of each targeted therapy. Based on the process of protein synthesis, we attempt to summarize the direct-effect targets including protein, RNA, and DNA.
METHODS
For this systematic review, relevant studies are assessed by searching in several databases including PubMed, Web of Science, Scopus, and Google Scholar. The publications of original researches are considered for screening.
RESULTS
Most drugs are protein-targeted such as molecule-based and monoclonal antibodies, including statins, ezetimibe, alirocumab, evolocumab, and evinacumab. Both antisense oligonucleotide (ASO) and small interfering RNA (siRNA) approaches, such as mipomersen, vupanorsen, inclisiran, and ARO-ANG3, are designed to reduce the number of mRNA transcripts and then degrade proteins. DNA-targeted therapies such as adeno-associated virus or CRISPR-Cas9 modification could be used to deliver or edit genes to address a genetic deficiency and improve the related phenotype.
CONCLUSION
While the therapies based on different targets including protein, RNA, and DNA are on different stages of development, the mechanisms of these novel therapies may provide new ideas for precision medicine.
Topics: Anticholesteremic Agents; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Oligonucleotides, Antisense; RNA
PubMed: 35712827
DOI: 10.1002/jcla.24552 -
European Journal of Clinical... Nov 2022Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG.
METHODS
Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022.
RESULTS
Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p < .001 I = 89.05%; p < .001); VLDL-C level (MD: -71.0%; 95%CI: -76.6%, -65.4%; p < .001 I = 94.1%; p < .001); Apo-B48 level (MD: -69.03%; 95%CI: -98.59.4%, -39.47%; p < .001, I = 93.51%; p < .001) and Apo-CIII level (MD: -80.0%; 95%CI: -97.5%, -62.5; p < .001 I = 94.1%; p < .001) with an increase in HDL-C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p < .001 I = 94.34%; p < .001) and in LDL-C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p < .001 I = 96.18%; p < .001) without a significant elevation of Apo-B100 level (MD: +4.58%, 95%CI: -5.64%, +14.79%; p = .380 I = 95.09%; p < .001) in 139 volanesorsen patients as compared to 100 placebo-treated controls. Most of adverse events were mild and related to local injection site reactions.
CONCLUSIONS
In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.
Topics: Apolipoprotein B-48; Apolipoprotein C-III; Cholesterol, LDL; Humans; Hyperlipidemias; Hypertriglyceridemia; Oligonucleotides; Oligonucleotides, Antisense; RNA, Messenger; Randomized Controlled Trials as Topic; Triglycerides
PubMed: 35851450
DOI: 10.1111/eci.13841 -
Gene Therapy Sep 2022Spinal muscular atrophy (SMA) is a severe childhood neuromuscular disease for which two genetic therapies, Nusinersen (Spinraza, an antisense oligonucleotide), and... (Meta-Analysis)
Meta-Analysis
Spinal muscular atrophy (SMA) is a severe childhood neuromuscular disease for which two genetic therapies, Nusinersen (Spinraza, an antisense oligonucleotide), and AVXS-101 (Zolgensma, an adeno-associated viral vector of serotype 9 AAV9), have recently been approved. We investigated the pre-clinical development of SMA genetic therapies in rodent models and whether this can predict clinical efficacy. We have performed a systematic review of relevant publications and extracted median survival and details of experimental design. A random effects meta-analysis was used to estimate and compare efficacy. We stratified by experimental design (type of genetic therapy, mouse model, route and time of administration) and sought any evidence of publication bias. 51 publications were identified containing 155 individual comparisons, comprising 2573 animals in total. Genetic therapies prolonged survival in SMA mouse models by 3.23-fold (95% CI 2.75-3.79) compared to controls. Study design characteristics accounted for significant heterogeneity between studies and greatly affected observed median survival ratios. Some evidence of publication bias was found. These data are consistent with the extended average lifespan of Spinraza- and Zolgensma-treated children in the clinic. Together, these results support that SMA has been particularly amenable to genetic therapy approaches and highlight SMA as a trailblazer for therapeutic development.
Topics: Animals; Disease Models, Animal; Genetic Therapy; Mice; Muscular Atrophy, Spinal; Oligonucleotides, Antisense; Rodentia; Treatment Outcome
PubMed: 34611322
DOI: 10.1038/s41434-021-00292-4 -
Frontiers in Neurology 2021We sought to provide an overview of the published and currently ongoing movement disorders clinical trials employing gene therapy, defined as a technology aiming to...
We sought to provide an overview of the published and currently ongoing movement disorders clinical trials employing gene therapy, defined as a technology aiming to modulate the expression of one or more genes to achieve a therapeutic benefit. We systematically reviewed movement disorders gene therapy clinical trials from PubMed and ClinicalTrials.gov using a searching strategy that included Parkinson disease (PD), Huntington disease (HD), amino acid decarboxylase (AADC) deficiency, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dystonia, tremor, ataxia, and other movement disorders. Data extracted included study characteristics, investigational product, route of administration, safety/tolerability, motor endpoints, and secondary outcomes (i.e., neuroimaging, biomarkers). We identified a total of 46 studies focusing on PD (21 published and nine ongoing), HD (2 published and 5 ongoing), AADC deficiency (4 published and 2 ongoing), MSA (2 ongoing), and PSP (1 ongoing). In PD, intraparenchymal infusion of viral vector-mediated gene therapies demonstrated to be safe and showed promising preliminary data in trials aiming at restoring the synthesis of dopamine, enhancing the production of neurotrophic factors, or modifying the functional interaction between different nodes of the basal ganglia. In HD, monthly intrathecal delivery of an antisense oligonucleotide (ASO) targeting the huntingtin protein (HTT) mRNA proved to be safe and tolerable, and demonstrated a dose-dependent reduction of the cerebrospinal fluid levels of mutated HTT, while a small phase-I study testing implantable capsules of cells engineered to synthesize ciliary neurotrophic factor failed to show consistent drug delivery. In AADC deficiency, gene replacement studies demonstrated to be relatively safe in restoring catecholamine and serotonin synthesis, with promising outcomes. Ongoing movement disorders clinical trials are focusing on a variety of gene therapy approaches including alternative viral vector serotypes, novel recombinant genes, novel delivery techniques, and ASOs for the treatment of HD, MSA, and distinct subtypes of PD (LRRK2 mutation or GBA1 mutation carriers). Initial phase-I and -II studies tested the safety and feasibility of gene therapy in PD, HD, and AADC deficiency. The ongoing generation of clinical trials aims to test the efficacy of these approaches and explore additional applications for gene therapy in movement disorders.
PubMed: 33889127
DOI: 10.3389/fneur.2021.648532 -
Non-coding RNA Research Dec 2023At present, RNA-based therapy which includes therapies using non-coding RNAs (ncRNAs), antisense oligonucleotides (ASOs), and aptamers are gaining widespread attention... (Review)
Review
At present, RNA-based therapy which includes therapies using non-coding RNAs (ncRNAs), antisense oligonucleotides (ASOs), and aptamers are gaining widespread attention as possible ways to target genes in various cardiovascular diseases (CVDs), thereby serving as a promising therapeutic approach for CVDs and risk factors management. However, data are primarily in an early stage. A systematic review was carried out using literature from several databases (Pubmed, Cochrane, Scopus, and DOAJR) following the PRISMA guidelines. Of the 64 articles reviewed, 39 papers were included in this review with three main types of RNAs: aptamers, antisense oligonucleotides (ASOs), and small-interfering RNA (siRNA). All studies were human clinical trials. RNA-based therapies were demonstrated to be efficacious in treating various CVDs and controlling cardiovascular risk factors. They are generally safe and well-tolerated. However, data are still in the early stage and warrant further investigation.
PubMed: 37483458
DOI: 10.1016/j.ncrna.2023.06.002 -
Neurotherapeutics : the Journal of the... Mar 2022Evidence for nusinersen administration in adult 5q spinal muscular atrophy (5q-SMA) patients is scarce and based on real-world observational data. The present systematic... (Meta-Analysis)
Meta-Analysis
Evidence for nusinersen administration in adult 5q spinal muscular atrophy (5q-SMA) patients is scarce and based on real-world observational data. The present systematic review and meta-analysis aimed to explore the efficacy and safety of nusinersen in patients older than 12 years of age with 5q-SMA. We searched MEDLINE, EMBASE, the Cochrane Library, and grey literature through April 2021. Cross-sectional studies, case reports, review articles, and studies with follow-up less than 6 months were excluded. We included 12 records (seven case-series, five cohorts) representing 11 population cohorts and enrolling 428 SMA patients. We observed statistically significant improvements on motor function Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores at the longest follow-up assessments [SMD = 0.17(95% CI 0.01-0.33), SMD = 0.22(95% CI 0.06-0.38), respectively]. HFMSE and RULM significant improvements were also detected at the subgroup analysis during 10 and 14 months. HFMSE and RULM amelioration occurred earlier in patients with SMA type 3 or 4 during short-term analysis (≤ 6 months). 6-min walk tests (6MWT) and pulmonary function tests did not change. Minimal clinically important differences in HFMSE and RULM were observed in 43.3% (95% CI 34.5-52.3) and 38.9% (95% CI 27.7-50.7), respectively. Severe adverse events were reported in 2% (95% CI 0-5.8). Treatment withdrawal rate was 3% (95% CI 0.5-6.6). Despite the low quality of evidence and the unmet need for randomized data to establish the safety and efficacy of nusinersen in adults, our meta-analysis confirms that nusinersen is a valuable treatment option for older patients with longer-disease duration.Trial registration: PROSPERO database CRD42020223109.
Topics: Adult; Cross-Sectional Studies; Humans; Muscular Atrophy, Spinal; Oligonucleotides; Spinal Muscular Atrophies of Childhood
PubMed: 35178673
DOI: 10.1007/s13311-022-01200-3 -
Cells Mar 2023Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall... (Review)
Review
INTRODUCTION
Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) as a new hope for disease-modifying strategies. In this article, we aim to perform a review of studies investigating the efficacy and safety profile of GSTs in HCAs.
METHODS
A structured PubMed search on GSTs in HCAs from January 1993 up to October 2020 was performed. Inclusion and exclusion criteria were defined, and the selection process was conducted accordingly. The screening process was independently carried out by two authors and was initially based on title and abstract, followed by full-text reading. The risk-of-bias assessment was performed with SYRCLE's tool. A data extraction sheet was created to collect relevant information from each selected article.
RESULTS
The initial search yielded 262 papers, of which 239 were excluded. An additional article was obtained following reference scrutiny, resulting in a total of 24 articles for final analysis. Most studies were not clear on the tools used to assess bias. In SCA1, SCA2, MJD/SCA3 and SCA7, RNA interference (iRNA) and antisense oligonucleotide (ASO) therapies proved to be well tolerated and effective in suppressing mutant proteins, improving neuropathological features and the motor phenotype. In SCA6, the phenotype was improved, but no investigation of adverse effects was performed. In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed.
CONCLUSION
The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype . Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2.
Topics: Animals; Cerebellar Ataxia; Trinucleotide Repeats; Spinocerebellar Degenerations; Proteins
PubMed: 37048110
DOI: 10.3390/cells12071037 -
Journal of Psychiatric Research Dec 2023Depression, anxiety and PTSD appear to be risk factors for dementia, but it is unclear whether they are causal or prodromal. The inflammatory-mediated neurodegeneration... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Depression, anxiety and PTSD appear to be risk factors for dementia, but it is unclear whether they are causal or prodromal. The inflammatory-mediated neurodegeneration hypothesis suggests a causal link, proposing that mental illness is associated with an inflammatory response which, in turn, triggers neurodegenerative changes that lead to dementia. Existing meta-analyses have yet to examine inflammatory markers in depression, anxiety or PTSD with the view to exploring the inflammatory-mediated neurodegeneration hypothesis. The current meta-analysis therefore examined whether: a) depression, anxiety and PTSD are individually associated with inflammation, independently of comorbid mental illnesses and physical health problems with known inflammatory responses, and b) there are any similarities in the inflammatory profiles of these disorders in order to provide a basis for exploring inflammation in people with dementia who have a history of clinically-significant anxiety, depression or PTSD.
METHODS
PubMed, EMBASE, PsycINFO and CINAHL searches identified 64 eligible studies.
RESULTS
Depression is associated with an inflammatory response, with tentative evidence to suggest anxiety and PTSD are also associated with inflammation. However, the specific response may differ across these disorders.
LIMITATIONS
The data for anxiety, PTSD and multiple inflammatory markers were limited.
CONCLUSIONS
Depression, anxiety, and PTSD each appear to be associated with an inflammatory response in persons who do not have comorbid mental or physical health problems that are known to be associated with inflammation. Whether this inflammatory response underlies the increased risk of dementia in persons with a history of depression and anxiety, and possibly PTSD, remains to be determined.
Topics: Humans; Stress Disorders, Post-Traumatic; Depression; Anxiety; Inflammation; Dementia
PubMed: 37931509
DOI: 10.1016/j.jpsychires.2023.10.009 -
Cancers Jan 2021Transforming growth factor β (TGFβ) is a pleiotropic cytokine that participates in a wide range of biological functions. The alterations in the expression levels of... (Review)
Review
Transforming growth factor β (TGFβ) is a pleiotropic cytokine that participates in a wide range of biological functions. The alterations in the expression levels of this factor, or the deregulation of its signaling cascade, can lead to different pathologies, including cancer. A great variety of therapeutic strategies targeting TGFβ, or the members included in its signaling pathway, are currently being researched in cancer treatment. However, the dual role of TGFβ, as a tumor suppressor or a tumor-promoter, together with its crosstalk with other signaling pathways, has hampered the development of safe and effective treatments aimed at halting the cancer progression. This systematic literature review aims to provide insight into the different approaches available to regulate TGFβ and/or the molecules involved in its synthesis, activation, or signaling, as a cancer treatment. The therapeutic strategies most commonly investigated include antisense oligonucleotides, which prevent TGFβ synthesis, to molecules that block the interaction between TGFβ and its signaling receptors, together with inhibitors of the TGFβ signaling cascade-effectors. The effectiveness and possible complications of the different potential therapies available are also discussed.
PubMed: 33498521
DOI: 10.3390/cancers13030379