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International Journal of Antimicrobial... Mar 2024Peptide nucleic acids (PNAs) are synthetic molecules that are like DNA/RNA, but with different building blocks. PNAs target and bind to mRNAs and disrupt the function of... (Review)
Review
Peptide nucleic acids (PNAs) are synthetic molecules that are like DNA/RNA, but with different building blocks. PNAs target and bind to mRNAs and disrupt the function of a targeted gene, hence they have been studied as potential antibacterials. The aim of this systematic review was to provide an in-depth analysis of the current status of PNAs as antibacterial agents, define the characteristics of the effective PNA constructs, and address the gap in advancing PNAs to become clinically competent agents. Following the PRISMA model, four electronic databases were searched: Web of Science, PubMed, SciFinder and Scopus. A total of 627 articles published between 1994 and 2023 were found. After screening and a rigorous selection process using explicit inclusion and exclusion criteria, 65 scientific articles were selected, containing 656 minimum inhibitory concentration (MIC) data. The antibacterial activity of PNAs was assessed against 20 bacterial species. The most studied Gram-negative and Gram-positive bacteria were Escherichia coli (n=266) and Staphylococcus aureus (n=53), respectively. In addition, the effect of PNA design, including construct length, binding location, and carrier agents, on antibacterial activity was shown. Finally, antibacterial test models to assess the inhibitory effects of PNAs were examined, emphasising gaps and prospects. This systematic review provides a comprehensive assessment of the potential of PNAs as antibacterial agents and offers valuable insights for researchers and clinicians seeking novel therapeutic strategies in the context of increasing rates of antibiotic-resistant bacteria.
Topics: Anti-Bacterial Agents; Bacteria; Peptide Nucleic Acids; Staphylococcus aureus
PubMed: 38185398
DOI: 10.1016/j.ijantimicag.2024.107083 -
Brain Imaging and Behavior Oct 2021While C9orf72-specific imaging signatures have been proposed by both ALS and FTD research groups and considerable presymptomatic alterations have also been confirmed in... (Review)
Review
While C9orf72-specific imaging signatures have been proposed by both ALS and FTD research groups and considerable presymptomatic alterations have also been confirmed in young mutation carriers, considerable inconsistencies exist in the literature. Accordingly, a systematic review of C9orf72-imaging studies has been performed to identify consensus findings, stereotyped shortcomings, and unique contributions to outline future directions. A formal literature review was conducted according to the STROBE guidelines. All identified papers were individually reviewed for sample size, choice of controls, study design, imaging modalities, statistical models, clinical profiling, and identified genotype-associated pathological patterns. A total of 74 imaging papers were systematically reviewed. ALS patients with GGGGCC repeat expansions exhibit relatively limited motor cortex involvement and widespread extra-motor pathology. C9orf72 positive FTD patients often show preferential posterior involvement. Reports of thalamic involvement are relatively consistent across the various phenotypes. Asymptomatic hexanucleotide repeat carriers often exhibit structural and functional changes decades prior to symptom onset. Common shortcomings included sample size limitations, lack of disease-controls, limited clinical profiling, lack of genetic testing in healthy controls, and absence of post mortem validation. There is a striking paucity of longitudinal studies and existing presymptomatic studies have not evaluated the predictive value of radiological changes with regard to age of onset and phenoconversion. With the advent of antisense oligonucleotide therapies, the meticulous characterisation of C9orf72-associated changes has gained practical relevance. Neuroimaging offers non-invasive biomarkers for future clinical trials, presymptomatic ascertainment, diagnostic and prognostic applications.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; DNA Repeat Expansion; Frontotemporal Dementia; Humans; Magnetic Resonance Imaging; Proteins
PubMed: 33398779
DOI: 10.1007/s11682-020-00429-w -
Expert Opinion on Investigational Drugs Jul 2021Mood disorders are severe yet frequent psychiatric disorders worldwide, comprising major depressive disorder (MDD) and bipolar disorders (BD). Their treatment remains...
INTRODUCTION
Mood disorders are severe yet frequent psychiatric disorders worldwide, comprising major depressive disorder (MDD) and bipolar disorders (BD). Their treatment remains poorly effective. Recently, growing evidence for epigenetic mechanisms has emerged. Consequently, a great interest in a novel pharmacological class arose: RNA therapeutics.
AREAS COVERED
We conducted a systematic review of RNA therapeutics -antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), and micro-RNA (miRNA) therapeutics- for the treatment of mood disorders studied in pre-clinical animal models listed in PubMed, in clinical trials registered in ClinicalTrials.gov and available on the market by combining literature search and Food and Drug Administration and European Medicine Agency online databases. Eighteen pre-clinical studies investigated the antidepressant effects of RNA therapeutics. However, even though there is an increasing number of marketing authorizations and clinical trials for the past twenty years, no RNA therapeutic has reached the clinical development pipeline for the treatment of psychiatric disorders yet.
EXPERT OPINION
Several promising RNA therapeutics have been tested in pre-clinical studies for MDD, whereas no molecule has been developed for BD. There are several issues to address before reaching clinical development and new challenges include stratifying patient population and predicting therapeutic response.
Topics: Animals; Bipolar Disorder; Clinical Trials as Topic; Depressive Disorder, Major; Humans; Mood Disorders; RNA
PubMed: 33966550
DOI: 10.1080/13543784.2021.1928073 -
Genes Feb 2023Recently, several studies have highlighted a skewed prevalence of infectious diseases within the African continent. Furthermore, a growing number of studies have... (Review)
Review
Recently, several studies have highlighted a skewed prevalence of infectious diseases within the African continent. Furthermore, a growing number of studies have demonstrated unique genetic variants found within the African genome are one of the contributing factors to the disease severity of infectious diseases within Africa. Understanding the host genetic mechanisms that offer protection against infectious diseases provides an opportunity to develop unique therapeutic interventions. Over the past two decades, several studies have linked the 2'-5'-oligoadenylate synthetase (OAS) family with a range of infectious diseases. More recently, the gene has also been associated with disease severity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to a global pandemic. The OAS family serves as an antiviral factor through the interaction with Ribonuclease-Latent (RNase-L). This review explores the genetic variants observed within the genes and the associations with various viral infections and how previously reported ethnic-specific polymorphisms drive clinical significance. This review provides an overview of genetic association studies with a particular focus on viral diseases affecting individuals of African descent.
Topics: Humans; SARS-CoV-2; COVID-19; Adenine Nucleotides; Oligoribonucleotides
PubMed: 36833454
DOI: 10.3390/genes14020527 -
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 -
The Cochrane Database of Systematic... Jun 2024Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss... (Meta-Analysis)
Meta-Analysis Review
RATIONALE
Neovascular age-related macular degeneration (AMD) is a progressive eye disease characterized by choroidal neovascularization (CNV) and is a leading cause of vision loss and disability worldwide. Although intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is an effective treatment option that helps to prevent vision loss or to improve visual acuity in people with neovascular AMD, treatment imposes a significant financial burden on patients and healthcare systems. A biosimilar is a biological product that has been developed to be nearly identical to a previously approved biological product. The use of biosimilars may help reduce costs and so may increase patient access to effective biologic medicines with similar levels of safety to the drugs on which they are based.
OBJECTIVES
To assess the benefits and harms of anti-VEGF biosimilar agents compared with their corresponding anti-VEGF agents (i.e. the reference products) that have obtained regulatory approval for intravitreal injections in people with neovascular AMD.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registries together with reference checking and contact with study authors to identify studies that are included in the review. The latest search date was 2 June 2023.
ELIGIBILITY CRITERIA
We included randomized controlled trials (RCTs) that compared approved anti-VEGF biosimilars with their reference products for treating the eyes of adult participants (≥ 50 years) who had an active primary or recurrent choroidal neovascularization lesion secondary to neovascular AMD.
OUTCOMES
Our outcomes were: best-corrected visual acuity (BCVA), central subfield thickness (CST), vision-related quality of life, serious ocular and non-ocular adverse events (AE), treatment-emergent adverse events (TEAEs), anti-drug antibodies (ADAs), and serum concentrations of biosimilars and reference drugs.
RISK OF BIAS
We assessed the risk of bias (RoB) for seven outcomes reported in a summary of findings table by using the Cochrane RoB 2 tool.
SYNTHESIS METHODS
We synthesized results for each outcome using meta-analysis, where possible, by calculating risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. Where this was not possible due to the nature of the data, we summarized the results narratively. We used GRADE to assess the certainty of evidence for prespecified outcomes.
INCLUDED STUDIES
We included nine parallel-group multi-center RCTs that enrolled a total of 3814 participants (3814 participating eyes), with sample sizes that ranged from 160 to 705 participants per study. The mean age of the participants in these studies ranged from 67 to 76 years, and the proportion of women ranged from 26.5% to 58.7%. Ranibizumab (Lucentis) was the reference product in seven studies, and aflibercept (Eyelea) was the reference product in two others. All the included studies had been supported by industry. The follow-up periods ranged from 12 to 52 weeks (median 48 weeks). Five studies (56%) were conducted in multi-country settings across Europe, North America and Asia, two studies in India, and one each in Japan and the Republic of Korea. We judged all the included studies to have met high methodological standards.
SYNTHESIS OF RESULTS
With regard to efficacy, our meta-analyses demonstrated that anti-VEGF biosimilars for neovascular AMD resulted in little to no difference compared with the reference products for BCVA change at 8 to 12 weeks (MD -0.55 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% CI -1.17 to 0.07; 8 studies, 3603 participants; high-certainty evidence) and the proportion of participants who lost fewer than 15 letters in BCVA at 24 to 48 weeks (RR 0.99, 95% CI 0.98 to 1.01; 7 studies, 2658 participants; moderate-certainty evidence). Almost all participants (96.6% in the biosimilar group and 97.0% in the reference product group) lost fewer than 15 letters in BCVA. The evidence from two studies suggested that there was no evidence of difference between biosimilars and reference products in vision-related quality of life measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) summary scores at 24 to 48 weeks (MD 0.82, 95% CI -0.70 to 2.35; 2 studies, 894 participants; moderate-certainty evidence). With regard to the safety profile, meta-analyses also revealed little to no difference between anti-VEGF biosimilars and the reference products for the proportion of participants who experienced serious ocular AEs (RR 1.24, 95% CI 0.68 to 2.26; 7 studies, 3292 participants; moderate-certainty evidence), and for TEAEs leading to investigational product discontinuation or death (RR 0.96, 95% CI 0.63 to 1.46; 8 studies, 3497 participants; moderate-certainty evidence). Overall, 1.4% of participants in the biosimilar group and 1.2% in the reference product group experienced serious ocular adverse events. The most frequently documented serious ocular AEs were retinal hemorrhage and endophthalmitis. Although the evidence is of low certainty due to imprecision, meta-analysis suggested that anti-VEGF biosimilars led to no difference compared with the reference products for cumulative incidence of ADAs (RR 0.84, 95% CI 0.58 to 1.22; 8 studies, 3066 participants; low-certainty evidence) or mean maximum serum concentrations (MD 0.42 ng/mL, 95% CI -0.22 to 1.05; subgroup of 3 studies, 100 participants; low-certainty evidence). We judged the overall risk of bias to be low for all studies.
AUTHORS' CONCLUSIONS
In our review, low to high certainty evidence suggests that there is little to no difference, to date, between the anti-VEGF biosimilars approved for treating neovascular AMD and their reference products in terms of benefits and harms. While anti-VEGF biosimilars may be a viable alternative to reference products, current evidence for their use is based on a limited number of studies - particularly for comparison with aflibercept - with sparse long-term safety data, and infrequent assessment of quality of life outcomes. Our effect estimates and conclusions may be modified once findings have been reported from studies that are currently ongoing, and studies of biosimilar agents that are currently in development.
FUNDING
Cochrane Eyes and Vision US Project is supported by grant UG1EY020522, National Eye Institute, National Institutes of Health. Takeshi Hasegawa and Hisashi Noma were supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239).
REGISTRATION
Protocol available via doi.org/10.1002/14651858.CD015804.
Topics: Aged; Humans; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Aptamers, Nucleotide; Bevacizumab; Bias; Biosimilar Pharmaceuticals; Choroidal Neovascularization; Intravitreal Injections; Macular Degeneration; Randomized Controlled Trials as Topic; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor A; Visual Acuity; Middle Aged; Male; Female
PubMed: 38829176
DOI: 10.1002/14651858.CD015804.pub2 -
Medicina (Kaunas, Lithuania) Jun 2022We appreciate Ahmed Sami Aljabali and his colleagues for their interest and comments [...]. (Meta-Analysis)
Meta-Analysis
Reply to Aljabali et al. Comment on "Abbas et al. The Safety and Efficacy of Nusinersen in the Treatment of Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. 2022, , 213".
We appreciate Ahmed Sami Aljabali and his colleagues for their interest and comments [...].
Topics: Humans; Muscular Atrophy, Spinal; Oligonucleotides; Randomized Controlled Trials as Topic
PubMed: 35744055
DOI: 10.3390/medicina58060793 -
Medicina (Kaunas, Lithuania) Jun 2022We read with interest the article by Abbas et al. [...]. (Meta-Analysis)
Meta-Analysis
Comment on Abbas et al. The Safety and Efficacy of Nusinersen in the Treatment of Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. 2022, , 213.
We read with interest the article by Abbas et al. [...].
Topics: Humans; Muscular Atrophy, Spinal; Oligonucleotides; Randomized Controlled Trials as Topic
PubMed: 35744029
DOI: 10.3390/medicina58060766 -
JAMA Network Open Apr 2021A thorough understanding of the optimal role and sequence of agents for treatment of multiple myeloma (MM) requires knowledge of the use and rate of postprotocol...
IMPORTANCE
A thorough understanding of the optimal role and sequence of agents for treatment of multiple myeloma (MM) requires knowledge of the use and rate of postprotocol therapies in randomized clinical trials (RCTs).
OBJECTIVES
To examine the proportion of MM RCTs that reported postprotocol therapies and, among those, the percentage of patients who received no further therapy and how treatments differed between the control and intervention arms.
EVIDENCE REVIEW
The reporting of postprotocol therapies was systematically assessed in published MM RCTs using 3 databases (PubMed, Embase, and Cochrane Registry of Controlled Trials) for MM RCTs from January 1, 2005, to December 30, 2019. All MM RCTs were included, and all other studies, such as editorials, nonrandomized studies, and review articles, were excluded.
FINDINGS
A total of 103 RCTs were identified (47 251 patients); of these, 45 (43.7%) reported subsequent treatments in that publication or in any subsequent publication. Trials funded by pharmaceutical companies (26 of 47 [55.3%]) were more likely to report subsequent treatments than cooperative group studies (19 of 56 [33.9%]) (χ21,103 = 4.8; P = .03). Differences were found in the treatments received between the intervention and control arms of RCTs. When data were reported, 5150 of 9351 patients (54.9%) in RCTs of newly diagnosed MM and 2197 of 4501 patients (48.8%) in RCTs of relapsed/refractory MM received any subsequent therapy.
CONCLUSIONS AND RELEVANCE
Postprotocol therapies in MM RCTs are often not reported and, when they are, many patients receive no further therapy. Reporting guidelines for postprotocol therapies are needed.
Topics: Aftercare; Antineoplastic Combined Chemotherapy Protocols; Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Oligonucleotides; Progression-Free Survival; Randomized Controlled Trials as Topic; Research Design; Standard of Care
PubMed: 33909053
DOI: 10.1001/jamanetworkopen.2021.8084 -
Mini Reviews in Medicinal Chemistry 2020Recently, manipulation of gene expression and switching genes on or off highlight the potential of nucleic acid-based therapies (NA-BTs). Alzheimer's Disease (AD) is a... (Meta-Analysis)
Meta-Analysis
Recently, manipulation of gene expression and switching genes on or off highlight the potential of nucleic acid-based therapies (NA-BTs). Alzheimer's Disease (AD) is a common devastating neurodegenerative disease (NDs) responsible for 60-80% of all cases of dementia and predicted as a main public health concern among aged populations. The aim of this study was to outline the current research in the field of NA-BTs for the treatment of AD disabilities, including strategies to suppress the memory and learning defects, to promote recovery processes, and to reinforce social relationships in these patients. This review was performed via evaluating PubMed reported studies from January 2010 to November 2019. Also, reference lists were checked to find additional studies. All intermediation or complementarity of animal models, case-control and cohort studies, and controlled trials (CTs) on specific NA-BTs to AD were acceptable, although in vitro studies were excluded due to the considerable diversities and heterogeneities. After removing the duplicates according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) instruction, we merged remaining titles across search databases. There are 48 ongoing studies related to the application of nucleic acids in the treatment and diagnosis of AD where more consideration is given to DNA targeting strategies (18 targets for vectors and aptamers), antisense oligonucleotides (10 targets), micro-RNAs mimics (7 targets), antagomiRs (6 targets), small interferences-RNAs (5 targets), as well as mRNAs (2 targets) respectively. All of these targets are grouped into 4 categories according to their role in molecular pathways where amyloid-β (18 targets), neural survival (11 targets), memory and cognition (8 targets), and tau (3 targets) are more targeted pathways, respectively. With recent successes in the systemic delivery of nucleic acids via intravenous injection; it is worth investing in the production of new-generation medicines. There are still several challenges for NA-BTs including, their delivery to the effective modulators, mass production at low cost, sustaining efficacy and minimizing off-target effects. Regarding miRNA-based therapies, given the obvious involvement of miRNAs in numerous facets of brain disease, and the many sophisticated techniques for delivery to the brain, miRNA-based therapies will make new hope for the treatment of neurological diseases such as AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Antagomirs; Aptamers, Nucleotide; CRISPR-Cas Systems; Humans; MicroRNAs; Nucleic Acids; Oligonucleotides, Antisense; RNA, Small Interfering
PubMed: 32400332
DOI: 10.2174/1389557520666200513122357