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European Journal of Paediatric... Jul 2022This systematic review aimed to assess mid- and long-term (at least 12 months) real-world study data from all types of spinal muscular atrophy (SMA) patients treated... (Review)
Review
Mid- and long-term (at least 12 months) follow-up of patients with spinal muscular atrophy (SMA) treated with nusinersen, onasemnogene abeparvovec, risdiplam or combination therapies: A systematic review of real-world study data.
OBJECTIVES
This systematic review aimed to assess mid- and long-term (at least 12 months) real-world study data from all types of spinal muscular atrophy (SMA) patients treated with any of the approved drugs or combination therapies.
METHODS
A systematic literature search was carried out in five databases. Two authors selected the studies based on pre-defined selection criteria and independently graded the risk of bias at study level.
RESULTS
Five hundred forty-six records were identified in the literature search and 22 studies (in 26 publications) were included in the analysis. Nusinersen, onasemnogene abeparvovec and combination therapies improved motor endpoints in SMA type 1 patients. SMA type 2 to type 4 patients treated with nusinersen showed stabilisation or small improvements in motor endpoints with some deterioration observed. Quality of life endpoints, such as respiratory and nutritional support were poorly reported on. Drug-related adverse events occurred rarely in all types of SMA patients with all assessed drugs. Mid- and long-term studies on risdiplam could not be identified.
CONCLUSIONS
The large quantity of missing data and heterogeneity of studies hinder comparability. Although stability and further improvement on the long-term is still uncertain, the results from the included evidence, as well as from pivotal trials show a striking contrast to the natural progression of the disease.
Topics: Follow-Up Studies; Humans; Muscular Atrophy, Spinal; Oligonucleotides; Quality of Life; Spinal Muscular Atrophies of Childhood
PubMed: 35533607
DOI: 10.1016/j.ejpn.2022.04.006 -
CNS Neuroscience & Therapeutics Aug 2022Toll-like receptor (TLR) agonist polyinosinic-polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Toll-like receptor (TLR) agonist polyinosinic-polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence supporting its exact mechanism of action is unclear.
METHODS
We evaluated the neuroprotective role of poly I:C by assessing CI indicators such as brain infarct volume (BIV), neurological deficit score (N.S.), and signaling pathway proteins. Moreover, we performed a narrative review to illustrate the mechanism of action of TLRs and their role in CI. Our search identified 164 articles and 10 met the inclusion criterion.
RESULTS
Poly I:C reduces BIV and N.S. (p = 0.00 and p = 0.03). Interestingly, both pre- and post-conditioning decrease BIV (preC p = 0.04 and postC p = 0.00) and N.S. (preC p = 0.03 and postC p = 0.00). Furthermore, poly I:C upregulates TLR3 [SMD = 0.64; CIs (0.56, 0.72); p = 0.00], downregulates nuclear factor-κB (NF-κB) [SMD = -1.78; CIs (-2.67, -0.88); p = 0.0)], and tumor necrosis factor alpha (TNF-α) [SMD = -16.83; CIs (-22.63, -11.02); p = 0.00].
CONCLUSION
We showed that poly I:C is neuroprotective and acts via the TLR3/NF-κB/TNF-α pathway. Our review indicated that suppressing TLR 2/4 may illicit neuroprotection against CI. Further research on simultaneous activation of TLR3 with poly I:C and suppression of TLR 2/4 might open new vistas for the development of therapeutics against CI.
Topics: Animals; Brain Infarction; Brain Injuries; Brain Ischemia; Cerebral Infarction; NF-kappa B; Neuroprotective Agents; Poly I-C; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 3; Tumor Necrosis Factor-alpha
PubMed: 35510663
DOI: 10.1111/cns.13851 -
Analytical Chemistry Jun 2022Aptamers have been the subject of more than 144 000 papers to date. However, there has been a growing concern that discrepancies in the reporting of aptamer research... (Review)
Review
Aptamers have been the subject of more than 144 000 papers to date. However, there has been a growing concern that discrepancies in the reporting of aptamer research limit the reliability of these reagents for research and other applications. These observations noting inconsistencies in the use of our RNA antilysozyme aptamer served as an impetus for our systematic review of the reporting of aptamer sequences in the literature. Our detailed examination of the literature citing the RNA antilysozyme aptamer revealed that 93% of the 61 publications reviewed reported unexplained altered sequences with 96% of those using DNA variants. The 10 most cited aptamers were examined using a standardized methodology in order to categorize the extent to which the sequences themselves and altered sequences were adequately described in the literature. Our review of 780 aptamer publications spanned decades, multiple journals, and research groups and revealed that 41% of the papers reported unexplained sequence alterations or omitted sequences. We identified 10 common categories of sequence alterations including deletions, substitutions, and additions, among others. Overall, our findings can be used as a starting point for building better practices in author submissions and publication standards, elevating the rigor and reproducibility of aptamer research.
Topics: Aptamers, Nucleotide; RNA; Reproducibility of Results; SELEX Aptamer Technique
PubMed: 35420426
DOI: 10.1021/acs.analchem.1c04407 -
Medicina (Kaunas, Lithuania) Feb 2022: Spinal muscular atrophy (SMA) is a neurodegenerative disease that leads to progressive proximal muscle weakness and muscle atrophy. To assess the beneficial and... (Meta-Analysis)
Meta-Analysis Review
: Spinal muscular atrophy (SMA) is a neurodegenerative disease that leads to progressive proximal muscle weakness and muscle atrophy. To assess the beneficial and adverse effects of nusinersen, a promising intervention for SMA, we conducted a systematic search and meta-analysis of the published randomized control trials (RCTs) of nusinersen for SMA. : Utilizing the Preferred Reporting for Systematic Review and Meta-Analysis (PRISMA), we searched PubMed, Scopus, Web of Science, Cochrane Central, and Clinicaltrials.gov from inception to 22 July 2021. : Three RCTs satisfying the inclusion and exclusion criteria covered 274 patients: 178 patients in the nusinersen group. Our results show a significant risk difference (RD) in the motor milestone response (RD: 0.51; 95% CI: 0.39, 0.62; < 0.00001) and improvement in the HINE-2 score (RD: 0.26; 95% CI: 0.12, 0.40; < 0.0003) in the nusinersen group compared to the control group. Moreover, a significant decrease in the risk ratio (RR) for severe adverse events (RR: 0.72; 95% CI: 0.57, 0.92; = 0.007) and any adverse event leading to treatment discontinuation (RR: 0.40; 95% CI: 0.22, 0.74; = 0.004) was observed. An insignificant result was found for any adverse effects (RR: 0.93; 95% CI: 0.97, 1.01; = 0.14) and for serious adverse effects (RR: 0.81; 95% CI: 0.60, 1.07; = 0.14). : This review provides evidence that nusinersen treatment was effective in treatment for infants with SMA and was associated with fewer severe adverse events; however, more RCTs are needed to establish evidence.
Topics: Humans; Infant; Muscular Atrophy, Spinal; Oligonucleotides; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 35208537
DOI: 10.3390/medicina58020213 -
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 -
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 -
Neuroscience and Biobehavioral Reviews Oct 2021Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as... (Review)
Review
Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as schizophrenia. Rodent models of mIA have explored possible mechanisms underlying this paradigm and provide a vital tool for preclinical research. However, a comprehensive analysis of the molecular changes that occur in mIA-models is lacking, hindering identification of robust clinical targets. This systematic review assesses mIA-driven transcriptomic and epigenomic alterations in specific offspring brain regions. Across 118 studies, we focus on 88 candidate genes and show replicated changes in expression in critical functional areas, including elevated inflammatory markers, and reduced myelin and GABAergic signalling proteins. Further, disturbed epigenetic markers at nine of these genes support mIA-driven epigenetic modulation of transcription. Overall, our results demonstrate that current outcome measures have direct relevance for the hypothesised pathology of schizophrenia and emphasise the importance of mIA-models in contributing to the understanding of biological pathways impacted by mIA and the discovery of new drug targets.
Topics: Animals; Behavior, Animal; Brain; Disease Models, Animal; Epigenesis, Genetic; Epigenomics; Female; Gene Expression; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Rodentia
PubMed: 34280428
DOI: 10.1016/j.neubiorev.2021.07.015 -
Journal of Experimental & Clinical... Jun 2021Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological... (Review)
Review
Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological complexities surrounding glioblastoma, lymphocytes that infiltrate the brain to develop durable immunity with memory will be key. Polyinosinic:polycytidylic acid, or poly(I:C), and its derivative poly-ICLC could serve as a priming or boosting therapy to unleash lymphocytes and other factors in the (immuno)therapeutic armory against glioblastoma. Here, we present a systematic review on the effects and efficacy of poly(I:C)/poly-ICLC for glioblastoma treatment, ranging from preclinical work on cellular and murine glioblastoma models to reported and ongoing clinical studies. MEDLINE was searched until 15 May 2021 to identify preclinical (glioblastoma cells, murine models) and clinical studies that investigated poly(I:C) or poly-ICLC in glioblastoma. A systematic review approach was conducted according to PRISMA guidelines. ClinicalTrials.gov was queried for ongoing clinical studies. Direct pro-tumorigenic effects of poly(I:C) on glioblastoma cells have not been described. On the contrary, poly(I:C) changes the immunological profile of glioblastoma cells and can also kill them directly. In murine glioblastoma models, poly(I:C) has shown therapeutic relevance as an adjuvant therapy to several treatment modalities, including vaccination and immune checkpoint blockade. Clinically, mostly as an adjuvant to dendritic cell or peptide vaccines, poly-ICLC has been demonstrated to be safe and capable of eliciting immunological activity to boost therapeutic responses. Poly-ICLC could be a valuable tool to enhance immunotherapeutic approaches for glioblastoma. We conclude by proposing several promising combination strategies that might advance glioblastoma immunotherapy and discuss key pre-clinical aspects to improve clinical translation.
Topics: Animals; Brain Neoplasms; Cancer Vaccines; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Glioblastoma; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Mice; Poly I-C; Polylysine
PubMed: 34172082
DOI: 10.1186/s13046-021-02017-2 -
Medicine May 2021Pain in the tendons or ligaments is extremely common, accounting for 30% of the causes of visiting general practitioners. Polydeoxyribonucleotide (PDRN) is emerging as a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pain in the tendons or ligaments is extremely common, accounting for 30% of the causes of visiting general practitioners. Polydeoxyribonucleotide (PDRN) is emerging as a new treatment for musculoskeletal pain. However, the effects of PDRN in patients with tendon or ligament pain are unclear. Therefore, this study aimed to determine the impact of PDRN in patients with tendon or ligament pain through a meta-analysis.
METHODS
Electronic literature search of PubMed, Embase, SCOPUS, and Cochrane Library databases of all articles on PDRN treatment for patients with tendon or ligament pain published in the English language from inception until January 31, 2020. The search identified 262 citations.
RESULTS
One randomized controlled trial and 3 retrospective observational studies were included. Pain due to tendon or ligament disorders showed significant improvement after PDRN injection (standardized mean difference [SMD] = -1.43, 95% confidence interval [CI] = -1.80 to -1.06, P < .00001). In the subanalysis of patients with rotator cuff tendinopathy, rotator cuff tendinopathy-induced pain significantly improved (SMD = -2.34, 95% CI = -3.61 to -1.07, P = .0003) after PDRN injection. However, there was no difference in shoulder pain and disability index score and strength of shoulder abduction in patients with rotator cuff tendinopathy (shoulder pain and disability index score, SMD = 1.16, 95% CI = -1.20 to 3.52, P = .34; strength of shoulder abduction, SMD = 0.42, 95% CI = -0.03 to 0.88, P = .07).
CONCLUSION
Effective pain relief was achieved in patients with tendon or ligament disorders after PDRN injection. To more precisely determine this effect, a meta-analysis with a larger number of clinical trials is warranted.
Topics: Analgesics; Humans; Injections; Ligaments; Musculoskeletal Pain; Pain Measurement; Polydeoxyribonucleotides; Tendinopathy; Treatment Outcome
PubMed: 34106615
DOI: 10.1097/MD.0000000000025792 -
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