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Frontiers in Immunology 2022Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in... (Meta-Analysis)
Meta-Analysis
Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in clinical settings, a meta-analysis of 255 clinical trials was performed. A total of 7,289 patients are planned to be dosed. AAV2 was the most dominantly used serotype (29.8%, n=72), and 8.3% (n=20) of trials used engineered capsids. 38.7% (n=91) of trials employed neutralizing antibody assays for patient enrollment, while 15.3% (n=36) used ELISA-based total antibody assays. However, there was high variability in the eligibility criteria with cut-off tiers ranging from 1:1 to 1:1,600. To address potential immunogenicity, 46.3% (n=118) of trials applied immunosuppressants (prophylactic or reactive), while 32.7% (n=18) of CNS and 37.5% (n=24) of ocular-directed trials employed immunosuppressants, possibly due to the immune-privileged status of CNS and retina. There were a total of 11 patient deaths across 8 trials, and 18 out of 30 clinical holds were due to toxicity findings in clinical studies. 30.6% (n=78) of trials had treatment-emergent serious adverse events (TESAEs), with hepatotoxicity and thrombotic microangiopathy (systemic delivery) and neurotoxicity (CNS delivery) being the most prominent. Additionally, the durability of gene therapy may be impacted by two distinct decline mechanisms: 1) rapid decline presumably due to immune responses; or 2) gradual decline due to vector dilution. The durability varied significantly depending on disease indication, dose, serotypes, and patient individuals. Most CNS (90.0%) and muscle trials (73.3%) achieved durable transgene expression, while only 43.6% of ocular trials had sustained clinical outcomes. The rAAV production system can affect rAAV quality and thus immunogenicity and toxicity. Out of 186 trials that have disclosed production system information, 63.0% (n=126) of trials used the transient transfection of the HEK293/HEK293T system, while 18.0% (n=36) applied the baculovirus/Sf9 (rBac/Sf9) system. There were no significant differences in TESAEs and durability between AAV generated by rBac/Sf9 and HEK293/HEK293T systems. In summary, rAAV immunogenicity and toxicity poses significant challenges for clinical development of rAAV gene therapies, and it warrants collaborative efforts to standardize monitoring/measurement methods, design novel strategies to overcome immune responses, and openly share relevant information.
Topics: Humans; Dependovirus; HEK293 Cells; Genetic Vectors; Genetic Therapy; Immunosuppressive Agents
PubMed: 36389770
DOI: 10.3389/fimmu.2022.1001263 -
Progress in Lipid Research Apr 2023Alzheimer's disease (AD) diagnosis is based on invasive and expensive biomarkers. Regarding AD pathophysiological mechanisms, there is evidence of a link between AD and... (Review)
Review
Alzheimer's disease (AD) diagnosis is based on invasive and expensive biomarkers. Regarding AD pathophysiological mechanisms, there is evidence of a link between AD and aberrant lipid homeostasis. Alterations in lipid composition have been observed in blood and brain samples, and transgenic mouse models represent a promising approach. Nevertheless, there is great variability among studies in mice for the determination of different types of lipids in targeted and untargeted methods. It could be explained by the different variables (model, age, sex, analytical technique), and experimental conditions used. The aim of this work is to review the studies on lipid alteration in brain tissue and blood samples from AD mouse models, focusing on different experimental parameters. As result, great disparity has been observed among the reviewed studies. Brain studies showed an increase in gangliosides, sphingomyelins, lysophospholipids and monounsaturated fatty acids and a decrease in sulfatides. In contrast, blood studies showed an increase in phosphoglycerides, sterols, diacylglycerols, triacylglycerols and polyunsaturated fatty acids, and a decrease in phospholipids, lysophospholipids and monounsaturated fatty acids. Thus, lipids are closely related to AD, and a consensus on lipidomics studies could be used as a diagnostic tool and providing insight into the mechanisms involved in AD.
Topics: Animals; Mice; Alzheimer Disease; Brain; Fatty Acids, Monounsaturated; Lipidomics; Lysophospholipids; Mice, Transgenic
PubMed: 36871907
DOI: 10.1016/j.plipres.2023.101223 -
Frontiers in Cellular and Infection... 2022Many individuals diagnosed with autism spectrum disorder (ASD) experience gastrointestinal (GI) dysfunction and show microbial dysbiosis. Variation in gut microbial... (Review)
Review
Many individuals diagnosed with autism spectrum disorder (ASD) experience gastrointestinal (GI) dysfunction and show microbial dysbiosis. Variation in gut microbial populations is associated with increased risk for GI symptoms such as chronic constipation and diarrhoea, which decrease quality of life. Several preclinical models of autism also demonstrate microbial dysbiosis. Given that much pre-clinical research is conducted in mouse models, it is important to understand the similarities and differences between the gut microbiome in humans and these models in the context of autism. We conducted a systematic review of the literature using PubMed, ProQuest and Scopus databases to compare microbiome profiles of patients with autism and transgenic (NL3, Shank3 KO, 15q dup), phenotype-first (BTBR) and environmental (Poly I:C, Maternal Inflammation Activation (MIA), valproate) mouse models of autism. Overall, we report changes in fecal microbial communities relevant to ASD based on both clinical and preclinical studies. Here, we identify an overlapping cluster of genera that are modified in both fecal samples from individuals with ASD and mouse models of autism. Specifically, we describe an increased abundance of , , and and a decrease in genera in both humans and rodents relevant to this disorder. Studies in both humans and mice highlighted multidirectional changes in abundance (i.e. in some cases increased abundance whereas other reports showed decreases) for several genera including , , , and , suggesting that these genera may be susceptible to modification in autism. Identification of these microbial profiles may assist in characterising underlying biological mechanisms involving host-microbe interactions and provide future therapeutic targets for improving gut health in autism.
Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; Dysbiosis; Gastrointestinal Diseases; Gastrointestinal Microbiome; Humans; Mice; Microfilament Proteins; Nerve Tissue Proteins; Quality of Life
PubMed: 35846755
DOI: 10.3389/fcimb.2022.905841 -
BMJ Open Diabetes Research & Care May 2020Mouse models are frequently used to study diabetes-associated ulcers, however, whether these models accurately simulate impaired wound healing has not been thoroughly... (Meta-Analysis)
Meta-Analysis Review
Mouse models are frequently used to study diabetes-associated ulcers, however, whether these models accurately simulate impaired wound healing has not been thoroughly investigated. This systematic review aimed to determine whether wound healing is impaired in mouse models of diabetes and assess the quality of the past research. A systematic literature search was performed of publicly available databases to identify original articles examining wound healing in mouse models of diabetes. A meta-analysis was performed to examine the effect of diabetes on wound healing rate using random effect models. A meta-regression was performed to examine the effect of diabetes duration on wound healing impairment. The quality of the included studies was also assessed using two newly developed tools. 77 studies using eight different models of diabetes within 678 non-diabetic and 720 diabetic mice were included. Meta-analysis showed that wound healing was impaired in all eight models. Meta-regression suggested that longer duration of diabetes prior to wound induction was correlated with greater degree of wound healing impairment. Pairwise comparisons suggested that non-obese diabetic mice exhibited more severe wound healing impairment compared with mice, streptozotocin-induced diabetic mice or high-fat fed mice at an intermediate stage of wound healing (p<0.01). Quality assessment suggested that the prior research frequently lacked incorporation of key clinically relevant characteristics. This systematic review suggested that impaired wound healing can be simulated in many different mouse models of diabetes but these require further refinement to become more clinically relevant.
Topics: Animals; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Mice; Ulcer; Wound Healing
PubMed: 32467222
DOI: 10.1136/bmjdrc-2019-000982 -
International Journal of Molecular... Oct 2022Initially, natural antisense transcripts (NATs, natRNAs, or asRNAs) were considered repressors; however, their functions in gene regulation are diverse. Positive,... (Review)
Review
Initially, natural antisense transcripts (NATs, natRNAs, or asRNAs) were considered repressors; however, their functions in gene regulation are diverse. Positive, negative, or neutral correlations to the cognate gene expression have been noted. Although the first studies were published about 50 years ago, there is still much to be investigated regarding antisense transcripts in plants. A systematic review of scientific publications available in the Web of Science databases was conducted to contextualize how the studying of antisense transcripts has been addressed. Studies were classified considering three categories: "Natural antisense" (208), artificial antisense used in "Genetic Engineering" (797), or "Natural antisense and Genetic Engineering"-related publications (96). A similar string was used for a systematic search in the NCBI Gene database. Of the 1132 antisense sequences found for plants, only 0.8% were cited in PubMed and had antisense information confirmed. This value was the lowest when compared to fungi (2.9%), bacteria (2.3%), and mice (54.1%). Finally, we present an update for the cis-NATs identified in spp. Of the 1413 antisense transcripts found in different experiments, 25 showed concordant expressions, 22 were discordant, 1264 did not correlate with the cognate genes, and 102 presented variable results depending on the experiment.
Topics: RNA, Antisense; RNA, Plant; Saccharum; Transcription Factors; Transcription, Genetic
PubMed: 36232906
DOI: 10.3390/ijms231911603 -
Molecular Biotechnology Jul 2023Emerging infectious diseases have vigorously devastated the global economy and health sector; cost-effective plant-based vaccines (PBV) can be the potential solution to... (Review)
Review
Emerging infectious diseases have vigorously devastated the global economy and health sector; cost-effective plant-based vaccines (PBV) can be the potential solution to withstand the current health economic crisis. The prominent role of tobacco as an efficient expression system for PBV has been well-established for decades, through this review we highlight the importance of tobacco-based vaccines (TBV) against evolving infectious diseases in humans. Studies focusing on the use of TBV for human infectious diseases were searched in PubMed, Google Scholar, and science direct from 1995 to 2021 using the keywords Tobacco-based vaccines OR transgenic tobacco OR Nicotiana benthamiana vaccines AND Infectious diseases or communicable diseases. We carried out a critical review of the articles and studies that fulfilled the eligibility criteria and were included in this review. Of 976 studies identified, only 63 studies fulfilling the eligibility criteria were included, which focused on either the in vitro, in vivo, or clinical studies on TBV for human infectious diseases. Around 43 in vitro studies of 23 different infectious pathogens expressed in tobacco-based systems were identified and 23 in vivo analysis studies were recognized to check the immunogenicity of vaccine candidates while only 10 of these were subjected to clinical trials. Viral infectious pathogens were studied more than bacterial pathogens. From our review, it was evident that TBV can be an effective health strategy to combat the emerging viral infectious diseases which are very difficult to manage with the current health facilities. The timely administration of cost-effective TBV can prevent the outburst of viral infections, thereby can protect the global healthcare system to a greater extent.
Topics: Humans; Nicotiana; Vaccines; Vaccines, Virus-Like Particle; Malaria Vaccines; Virus Diseases
PubMed: 36528727
DOI: 10.1007/s12033-022-00627-5 -
Drug Testing and Analysis Feb 2023Gene therapy uses genetic modification of cells to produce a therapeutic effect. Defective or missing genes can be repaired or replaced, or gene expression can be... (Review)
Review
Gene therapy uses genetic modification of cells to produce a therapeutic effect. Defective or missing genes can be repaired or replaced, or gene expression can be modified using a variety of technologies. Repair of defective genes can be achieved using specialized gene editing tools. Gene addition promotes gene expression by introducing synthetic copies of genes of interest (transgenes) into cells where they are transcribed and translated into therapeutic proteins. Protein production can also be modified using therapies that regulate gene expression. Gene therapy is currently prohibited in both human and equine athletes because of the potential to induce production of performance-enhancing proteins in the athlete's body, also referred to as "gene doping." Detection of gene doping is challenging and necessitates development of creative, novel analytical methods for doping control. Methods for detection of gene doping must be specific to and will vary depending on the type of gene therapy. The purpose of this paper is to present the results of a systematic review of gene editing, gene therapy, and detection of gene doping in horses. Based on the published literature, gene therapy has been administered to horses in a large number of experimental studies and a smaller number of clinical cases. Detection of gene therapy is possible using a combination of PCR and sequencing technologies. This summary can provide a basis for discussion of appropriate and inappropriate uses for gene therapy in horses by the veterinary community and guide expansion of methods to detect inappropriate uses by the regulatory community.
Topics: Animals; Doping in Sports; Genetic Therapy; Horses; Polymerase Chain Reaction; Transgenes
PubMed: 36269665
DOI: 10.1002/dta.3394 -
Frontiers in Nutrition 2022Nutritious foods are essential for human health and development. However, malnutrition and hidden hunger continue to be a challenge globally. In most developing... (Review)
Review
Nutritious foods are essential for human health and development. However, malnutrition and hidden hunger continue to be a challenge globally. In most developing countries, access to adequate and nutritious food continues to be a challenge. Although hidden hunger is less prevalent in developed countries compared to developing countries where iron (Fe) and zinc (Zn) deficiencies are common. The United Nations (UN) 2nd Sustainable Development Goal was set to eradicate malnutrition and hidden hunger. Hidden hunger has led to numerous cases of infant and maternal mortalities, and has greatly impacted growth, development, cognitive ability, and physical working capacity. This has influenced several countries to develop interventions that could help combat malnutrition and hidden hunger. Interventions such as dietary diversification and food supplementation are being adopted. However, fortification but mainly biofortification has been projected to be the most sustainable solution to malnutrition and hidden hunger. Plant-based foods (PBFs) form a greater proportion of diets in certain populations; hence, fortification of PBFs is relevant in combating malnutrition and hidden hunger. Agronomic biofortification, plant breeding, and transgenic approaches are some currently used strategies in food crops. Crops such as cereals, legumes, oilseeds, vegetables, and fruits have been biofortified through all these three strategies. The transgenic approach is sustainable, efficient, and rapid, making it suitable for biofortification programs. Omics technology has also been introduced to improve the efficiency of the transgenic approach.
PubMed: 36570169
DOI: 10.3389/fnut.2022.1043655 -
Frontiers in Oncology 2024Over the past years, there has been a growing interest in the role of immunotherapy in locally advanced (LA) and recurrent and metastatic head and neck squamous cell...
INTRODUCTION
Over the past years, there has been a growing interest in the role of immunotherapy in locally advanced (LA) and recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). High-quality data from prospective trials are lacking for the elderly subpopulation. This systematic review and meta-analysis aims to review the efficacy and safety of immunotherapy in older patients.
METHODS
A systematic literature search was conducted. Randomized clinical trials providing outcome data on a subgroup of elderly (>65 years old) were available for meta-analysis. Primary outcomes of interest were OS and PFS for efficacy analysis.
RESULTS
Seven studies were included in the systematic review and four in the efficacy analysis. The pooled analysis of OS and PFS showed a consistent benefit (HR 0.78 and 0.91, respectively).
CONCLUSIONS
Immunotherapy may be an effective and well-tolerated treatment option in the elderly population, but more prospective and randomized data are needed.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO (CRD42022333891).
PubMed: 38800381
DOI: 10.3389/fonc.2024.1395838 -
Immunology Letters Jul 2020Notch pathway is highly conserved across species and is involved in the regulation of cell differentiation and activity both in embryonic development and adult life....
BACKGROUND
Notch pathway is highly conserved across species and is involved in the regulation of cell differentiation and activity both in embryonic development and adult life. Notch signaling has an important role in the development of hematopoietic stem cells and their differentiation to committed lineages, as well as in the regulation of several non-hematopoietic cell lines.
OBJECTIVE
As Notch signaling has been implicated in various inflammatory and autoimmune diseases, it is of interest to elucidate what role do Notch receptors and ligands have in inflammatory arthritides.
METHODS
We performed a search on the role of Notch receptors (1-4) and Notch ligands Delta-like (DLL) 1, 3, 4 and Jagged (Jag) 1 and 2 in animal models of inflammatory arthritis and most common types of human inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis). The initial search identified 135 unique articles, of which 24 were ultimately deemed relevant and included in this systematic review.
RESULTS
Overall, identified articles describe roles for Notch ligands and receptors in inflammatory arthritis, with Notch activation resulting in enhanced Th1/17 polarization, osteoclast differentiation, macrophage activation and fibroblast-like synoviocyte proliferation. However, the inhibitory role of Notch signaling, especially by Jag1 is also described.
CONCLUSION
There is evidence that Notch pathway activation affects multiple cell lineages present within the arthritic environment, therefore potentially acting as one of the drivers of disease pathogenesis. Since cell lineage-selective transgenic mouse models and specific Notch receptor inhibitors are becoming increasingly available, it can be expected that future research will evaluate whether Notch signaling components initiate crucial pathogenic impulses and, therefore, present viable therapeutic targets in inflammatory arthritis.
Topics: Animals; Arthritis; Cell Differentiation; Disease Models, Animal; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Osteoclasts; Receptors, Notch; Serrate-Jagged Proteins; Th1 Cells; Th17 Cells
PubMed: 32325090
DOI: 10.1016/j.imlet.2020.04.010