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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 -
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 -
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 -
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 -
Journal of Alzheimer's Disease Reports Apr 2020Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is... (Review)
Review
Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1α deacetylation. Via PGC1α signaling, low-dose sildenafil likely suppresses β-secretase 1 expression and amyloid-β (Aβ) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. sildenafil protected neural mitochondria from Aβ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1β, interleukin-6, and tumor necrosis factor-α, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested Aβ levels reported significant improvements except the two that used the highest dosage, consistent with the dose-limiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1α signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.
PubMed: 32467879
DOI: 10.3233/ADR-200166 -
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 -
Neurobiology of Disease Mar 2024Transgenic models of familial Alzheimer's disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (Aβ)-induced pathology.... (Meta-Analysis)
Meta-Analysis Review
Transgenic models of familial Alzheimer's disease (AD) serve as valuable tools for probing the molecular mechanisms associated with amyloid-beta (Aβ)-induced pathology. In this meta-analysis, we sought to evaluate levels of phosphorylated tau (p-tau) and explore potential age-related variations in tau hyperphosphorylation, within mouse models of AD. The PubMed and Scopus databases were searched for studies measuring soluble p-tau in 5xFAD, APP/PSEN1, J20 and APP23 mice. Data were extracted and analyzed using standardized procedures. For the 5xFAD model, the search yielded 36 studies eligible for meta-analysis. Levels of p-tau were higher in 5xFAD mice relative to control, a difference that was evident in both the carboxy-terminal (CT) and proline-rich (PR) domains of tau. Age negatively moderated the relationship between genotype and CT phosphorylated tau in studies using hybrid mice, female mice, and preparations from the neocortex. For the APP/PSEN1 model, the search yielded 27 studies. Analysis showed tau hyperphosphorylation in transgenic vs. control animals, evident in both the CT and PR regions of tau. Age positively moderated the relationship between genotype and PR domain phosphorylated tau in the neocortex of APP/PSEN1 mice. A meta-analysis was not performed for the J20 and APP23 models, due to the limited number of studies measuring p-tau levels in these mice (<10 studies). Although tau is hyperphosphorylated in both 5xFAD and APP/PSEN1 mice, the effects of ageing on p-tau are contingent upon the model being examined. These observations emphasize the importance of tailoring model selection to the appropriate disease stage when considering the relationship between Aβ and tau, and suggest that there are optimal intervention points for the administration of both anti-amyloid and anti-tau therapies.
Topics: Mice; Female; Animals; Alzheimer Disease; Phosphorylation; Amyloid beta-Protein Precursor; Mice, Transgenic; tau Proteins; Amyloid beta-Peptides; Disease Models, Animal
PubMed: 38307366
DOI: 10.1016/j.nbd.2024.106427 -
Nutrients Feb 2020Several natural products have been reported to elicit beneficial effects against neurodegenerative disorders due to their vitamin E contents. However, the...
BACKGROUND
Several natural products have been reported to elicit beneficial effects against neurodegenerative disorders due to their vitamin E contents. However, the neuroprotective efficacy of palm oil or its tocotrienol-rich fraction (TRF) from the pre-clinical cell and animal studies have not been systematically reviewed.
METHODS
The protocol for this systematic review was registered in "PROSPERO" (CRD42019150408). This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The Medical Subject Heading (MeSH) descriptors of PubMed with Boolean operators were used to construct keywords, including ("Palm Oil"[Mesh]) AND "Nervous System"[Mesh], ("Palm Oil"[Mesh]) AND "Neurodegenerative Diseases"[Mesh], ("Palm Oil"[Mesh]) AND "Brain"[Mesh], and ("Palm Oil"[Mesh]) AND "Cognition"[Mesh], to retrieve the pertinent records from PubMed, Scopus, Web of Science and ScienceDirect from 1990 to 2019, while bibliographies, ProQuest and Google Scholar were searched to ensure a comprehensive identification of relevant articles. Two independent investigators were involved at every stage of the systematic review, while discrepancies were resolved through discussion with a third investigator.
RESULTS
All of the 18 included studies in this review (10 animal and eight cell studies) showed that palm oil and TRF enhanced the cognitive performance of healthy animals. In diabetes-induced rats, TRF and α-tocotrienol enhanced cognitive function and exerted antioxidant, anti-apoptotic and anti-inflammatory activities, while in a transgenic Alzheimer's disease (AD) animal model, TRF enhanced the cognitive function and reduced the deposition of β-amyloid by altering the expression of several genes related to AD and neuroprotection. In cell studies, simultaneous treatment with α-tocotrienols and neurotoxins improved the redox status in neuronal cells better than ϒ- and δ-tocotrienols. Both pre-treatment and post-treatment with α-tocotrienol relative to oxidative insults were able to enhance the survival of neuronal cells via increased antioxidant responses.
CONCLUSIONS
Palm oil and its TRF enhanced the cognitive functions of healthy animals, while TRF and α-tocotrienol enhanced the cognitive performance with attenuation of oxidative stress, neuroinflammation and apoptosis in diabetes-induced or transgenic AD animal models. In cell studies, TRF and α-tocotrienol exerted prophylactic neuroprotective effects, while α-tocotrienol exerted therapeutic neuroprotective effects that were superior to those of ϒ- and δ-tocotrienol isomers.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Antioxidants; Cells, Cultured; Chemical Fractionation; Cognition; Disease Models, Animal; Humans; Mice; Neuroprotective Agents; Oxidative Stress; Palm Oil; Phytotherapy; Rats; Tocotrienols
PubMed: 32085610
DOI: 10.3390/nu12020521 -
International Journal of Molecular... May 2021Bicistronic reporter assays have been instrumental for transgene expression, understanding of internal ribosomal entry site (IRES) translation, and identification of...
Bicistronic reporter assays have been instrumental for transgene expression, understanding of internal ribosomal entry site (IRES) translation, and identification of novel cap-independent translational elements (CITE). We observed a large methodological variability in the use of bicistronic reporter assays and data presentation or normalization procedures. Therefore, we systematically searched the literature for bicistronic IRES reporter studies and analyzed methodological details, data visualization, and normalization procedures. Two hundred fifty-seven publications were identified using our search strategy (published 1994-2020). Experimental studies on eukaryotic adherent cell systems and the cell-free translation assay were included for further analysis. We evaluated the following methodological details for 176 full text articles: the bicistronic reporter design, the cell line or type, transfection methods, and time point of analyses post-transfection. For the cell-free translation assay, we focused on methods of in vitro transcription, type of translation lysate, and incubation times and assay temperature. Data can be presented in multiple ways: raw data from individual cistrons, a ratio of the two, or fold changes thereof. In addition, many different control experiments have been suggested when studying IRES-mediated translation. In addition, many different normalization and control experiments have been suggested when studying IRES-mediated translation. Therefore, we also categorized and summarized their use. Our unbiased analyses provide a representative overview of bicistronic IRES reporter use. We identified parameters that were reported inconsistently or incompletely, which could hamper data reproduction and interpretation. On the basis of our analyses, we encourage adhering to a number of practices that should improve transparency of bicistronic reporter data presentation and improve methodological descriptions to facilitate data replication.
Topics: Animals; Genes, Reporter; Humans; Internal Ribosome Entry Sites; Protein Biosynthesis; Regulatory Sequences, Nucleic Acid; Ribosomes
PubMed: 34068921
DOI: 10.3390/ijms22105193