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Scientific Reports Mar 2018Antisense oligonucleotide (AON)-based therapies hold promise for a range of neurodegenerative and neuromuscular diseases and have shown benefit in animal models and... (Meta-Analysis)
Meta-Analysis
Antisense oligonucleotide (AON)-based therapies hold promise for a range of neurodegenerative and neuromuscular diseases and have shown benefit in animal models and patients. Success in the clinic is nevertheless still limited, due to unfavourable biodistribution and poor cellular uptake of AONs. Extensive research is currently being conducted into the formulation of AONs to improve delivery, but thus far there is no consensus on which of those strategies will be the most effective. This systematic review was designed to answer in an unbiased manner which delivery strategies most strongly enhance the efficacy of AONs in animal models of heritable neurodegenerative and neuromuscular diseases. In total, 95 primary studies met the predefined inclusion criteria. Study characteristics and data on biodistribution and toxicity were extracted and reporting quality and risk of bias were assessed. Twenty studies were eligible for meta-analysis. We found that even though the use of delivery systems provides an advantage over naked AONs, it is not yet possible to select the most promising strategies. Importantly, standardisation of experimental procedures is warranted in order to reach conclusions about the most efficient delivery strategies. Our best practice guidelines for future experiments serve as a step in that direction.
Topics: Animals; Disease Models, Animal; Drug Delivery Systems; Heredodegenerative Disorders, Nervous System; Neuromuscular Diseases; Oligonucleotides, Antisense
PubMed: 29520012
DOI: 10.1038/s41598-018-22316-7 -
Cardiovascular Drugs and Therapy Feb 2021Despite advances in the development of lipid-lowering therapies, clinical trials have shown that a significant residual risk of cardiovascular disease persists....
BACKGROUND
Despite advances in the development of lipid-lowering therapies, clinical trials have shown that a significant residual risk of cardiovascular disease persists. Specifically, new drugs are needed for non-responding or statin-intolerant subjects or patients considered at very high risk for cardiovascular events even though are already on treatment with the best standard of care.
RESULTS AND CONCLUSIONS
Besides, genetic and epidemiological studies and Mendelian randomization analyses have strengthened the linear correlation between the concentration of low-density lipoprotein cholesterol (LDL-C) and the incidence of cardiovascular events and highlighted various novel therapeutic targets. This review describes the novel strategies to reduce the levels of LDL-C, non-HDL-C, triglyceride, apolipoprotein B, and Lp(a), focusing on those developed using biotechnology-based strategies.
Topics: Antibodies, Monoclonal, Humanized; Apolipoproteins B; Cholesterol, LDL; Clinical Trials as Topic; Dyslipidemias; Genetic Therapy; Humans; Hypolipidemic Agents; Lysophospholipids; Oligonucleotides, Antisense; RNA, Small Interfering; Triglycerides
PubMed: 32519066
DOI: 10.1007/s10557-020-07017-6 -
Muscle & Nerve Mar 2022Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized... (Review)
Review
Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized published data on the clinical course of DMD by genotype. Using a systematic search implemented in Medline and Embase, 53 articles were identified that describe the clinical course of DMD, with pathogenic variants categorizable by exon skip or stop-codon readthrough amenability and outcomes presented by age. Outcomes described included those related to ambulatory, cardiac, pulmonary, or cognitive function. Estimates of the mean (95% confidence interval) age at LOA ranged from 9.1 (8.7-9.6) years among 90 patients amenable to skipping exon 53 to 11.5 (9.5-13.5) years among three patients amenable to skipping exon 8. Although function worsened with age, the impact of genotype was less clear for other outcomes (eg, forced vital capacity and left ventricular ejection fraction). Understanding the distribution of pathogenic variants is important for studies in DMD, as this research suggests major differences in the natural history of disease. In addition, specific details of the use of key medications, including corticosteroids, antisense oligonucleotides, and cardiac medications, should be reported.
Topics: Child; Dystrophin; Genotype; Humans; Muscular Dystrophy, Duchenne; Stroke Volume; Ventricular Function, Left
PubMed: 34878187
DOI: 10.1002/mus.27463 -
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 -
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 -
Journal of Neurochemistry Mar 2021The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization...
The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.
Topics: Amyloid; Amyloidosis, Familial; Animals; Gene Knockdown Techniques; Humans; Prealbumin
PubMed: 33155274
DOI: 10.1111/jnc.15233 -
The Cochrane Database of Systematic... Jul 2017Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for... (Review)
Review
BACKGROUND
Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.Opioids are used worldwide for the treatment of pain. They bind to opioid receptors in the central nervous system (mu, kappa, delta, and sigma) and can be agonists, antagonists, mixed agonist-antagonists, or partial agonists. Opioids are generally available in healthcare settings across most high-income countries, but access may be restricted in low- and middle-income countries. For example, opioids currently available in the UK include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are used in varying doses (generally based on body weight for paediatric patients) by means of parenteral, transmucosal, transdermal, or oral administration (immediate release or modified release). To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is a lower dose gradually titrated to effect in the child.
OBJECTIVES
To assess the analgesic efficacy and adverse events of opioids used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.
SELECTION CRITERIA
Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing opioids with placebo or an active comparator.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table.
MAIN RESULTS
No studies were eligible for inclusion in this review. We rated the quality of the evidence as very low. We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome.
AUTHORS' CONCLUSIONS
There was no evidence from randomised controlled trials to support or refute the use of opioids to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of opioids to treat chronic non-cancer pain in children and adolescents.We know from adult randomised controlled trials that some opioids, such as morphine and codeine, can be effective in certain chronic pain conditions.This means that no conclusions could be made about efficacy or harm in the use of opioids to treat chronic non-cancer pain in children and adolescents.
Topics: Adolescent; Analgesics, Opioid; Child; Child, Preschool; Chronic Pain; Humans; Infant; Infant, Newborn
PubMed: 28745394
DOI: 10.1002/14651858.CD012538.pub2 -
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 -
Journal of Cellular Physiology Apr 2019PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) has been shown to be aberrantly expressed in many types of cancer. Considering conflicting data, the... (Meta-Analysis)
Meta-Analysis
PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) has been shown to be aberrantly expressed in many types of cancer. Considering conflicting data, the current study was aimed to assess its potential role as a prognostic marker in malignant tumors. A comprehensive literature search of PubMed, Medline, and Web of Science was performed to identify all eligible studies describing the use of PANDAR as a prognostic factor for different types of cancer. Data related to overall survival (OS) and clinicopathologic features were collected and analyzed. The pooled hazard ratio (HR) and odds radio (OR) with a 95% confidence interval (CI) were used to estimate associations. Ten original studies containing 1,231 patients were included. The results showed that in patients with cancer, high PANDAR expression is correlated with lymph node metastasis (LNM; OR = 2.57; 95% CI, 1.76-3.81; p < 0.001), tumor stage (OR = 2.90; 95% CI, 1.25-6.75; p = 0.013), and tumor size (OR = 1.79; 95% CI, 1.11-2.91; p = 0.018). However, sensitivity analysis further demonstrated a significant association between high PANDAR expression and OS, both in multivariate and univariate analysis models (pooled HR 2.01; 95% CI, 1.17-3.44 and pooled HR 2.62; 95% CI, 1.98-3.47, respectively), after omitting one study. These results suggested that PANDAR expression might be indicative of advanced disease and poor prognosis in patients with cancer. Further studies are necessary to determine the value of this risk stratification biomarker in clinical management of patients with cancer.
Topics: Biomarkers, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Neoplasms; RNA, Long Noncoding; Risk Assessment; Risk Factors; Treatment Outcome; Tumor Burden
PubMed: 30191982
DOI: 10.1002/jcp.27179 -
The Cochrane Database of Systematic... Aug 2017Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines... (Review)
Review
BACKGROUND
Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can occur in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) relating to genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and for other unknown reasons.Antiepileptic (anticonvulsant) drugs, which were originally developed to treat convulsions in people with epilepsy, have in recent years been used to provide pain relief in adults for many chronic painful conditions and are now recommended for the treatment of chronic pain in the WHO list of essential medicines. Known side effects of antiepileptic drugs range from sweating, headache, elevated temperature, nausea, and abdominal pain to more serious effects including mental or motor function impairment.
OBJECTIVES
To assess the analgesic efficacy and adverse events of antiepileptic drugs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews as well as online clinical trial registries.
SELECTION CRITERIA
Randomised controlled trials, with or without blinding, by any route, treating chronic non-cancer pain in children and adolescents, comparing any antiepileptic drug with placebo or an active comparator.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods if data were available. We assessed the evidence using GRADE and created two 'Summary of findings' tables.
MAIN RESULTS
We included two studies with a total of 141 participants (aged 7 to 18 years) with chronic neuropathic pain, complex regional pain syndrome type 1 (CRPS-I), or fibromyalgia. One study investigated pregabalin versus placebo in participants with fibromyalgia (107 participants), and the other study investigated gabapentin versus amitriptyline in participants with CRPS-I or neuropathic pain (34 participants). We were unable to perform any quantitative analysis.Risk of bias for the two included studies varied, due to issues with randomisation (low to unclear risk), blinding of outcome assessors (low to unclear risk), reporting bias (low to unclear risk), the size of the study populations (high risk), and industry funding in the 'other' domain (low to unclear risk). We judged the remaining domains of sequence generation, blinding of participants and personnel, and attrition as low risk of bias. Primary outcomesOne study (gabapentin 900 mg/day versus amitriptyline 10 mg/day, 34 participants, for 6 weeks) did not report our primary outcomes (very low-quality evidence).The second study (pregabalin 75 to 450 mg/day versus placebo 75 to 450 mg/day, 107 participants, for 15 weeks) reported no significant change in pain scores for pain relief of 30% or greater between pregabalin 18/54 (33.3%), and placebo 16/51 (31.4%), P = 0.83 (very low-quality evidence). This study also reported Patient Global Impression of Change, with the percentage of participants feeling "much or very much improved" with pregabalin 53.1%, and placebo 29.5% (very low-quality evidence).We downgraded the evidence by three levels to very low for one of two reasons: due to the fact that there was no evidence to support or refute the use of the intervention, or that there were too few data and the number of events was too small to be meaningful. Secondary outcomesIn one small study, adverse events were uncommon: gabapentin 2 participants (2 adverse events); amitriptyline 1 participant (1 adverse event) (6-week trial). The second study reported a higher number of adverse events: pregabalin 38 participants (167 adverse events); placebo 34 participants (132 adverse events) (15-week trial) (very low-quality evidence).Withdrawals due to adverse events were infrequent in both studies: pregabalin (4 participants), placebo (4 participants), gabapentin (2 participants), and amitriptyline (1 participant) (very low-quality evidence).Serious adverse events were reported in both studies. One study reported only one serious adverse event (cholelithiasis and major depression resulting in hospitalisation in the pregabalin group) and the other study reported no serious adverse events (very low-quality evidence).There were few or no data for our remaining secondary outcomes (very low-quality evidence).We downgraded the evidence by three levels to very low due to too few data and the fact that the number of events was too small to be meaningful.
AUTHORS' CONCLUSIONS
This review identified only two small studies, with insufficient data for analysis.As we could undertake no meta-analysis, we were unable to comment about efficacy or harm from the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents. Similarly, we could not comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some antiepileptics, such as gabapentin and pregabalin, can be effective in certain chronic pain conditions.We found no evidence to support or refute the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents.
Topics: Adolescent; Amines; Amitriptyline; Anticonvulsants; Child; Chronic Pain; Complex Regional Pain Syndromes; Cyclohexanecarboxylic Acids; Fibromyalgia; Gabapentin; Humans; Neuralgia; Pregabalin; Randomized Controlled Trials as Topic; gamma-Aminobutyric Acid
PubMed: 28779491
DOI: 10.1002/14651858.CD012536.pub2