Characterization of Fabry mice treated with recombinant adeno-associated virus 2/8-mediated gene transfer

<p>Abstract</p> <p>Background</p> <p>Enzyme replacement therapy (ERT) with α-galactosidase A (α-Gal A) is currently the most effective therapeutic strategy for patients with Fabry disease, a lysosomal storage disease. However, ERT has limitations of a short half-life, requirement for frequent administration, and limited efficacy for patients with renal failure. Therefore, we investigated the efficacy of recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for a Fabry disease mouse model and compared it with that of ERT.</p> <p>Methods</p> <p>A pseudotyped rAAV2/8 vector encoding α-Gal A cDNA (rAAV2/8-hAGA) was prepared and injected into 18-week-old male Fabry mice through the tail vein. The α-Gal A expression level and globotriaosylceramide (Gb3) levels in the Fabry mice were examined and compared with Fabry mice with ERT. Immunohistochemical and ultrastructural studies were conducted.</p> <p>Results</p> <p>Treatment of Fabry mice with rAAV2/8-hAGA resulted in the clearance of accumulated Gb3 in tissues such as liver, spleen, kidney, heart, and brain with concomitant elevation of α-Gal A enzyme activity. Enzyme activity was elevated for up to 60 weeks. In addition, expression of the α-Gal A protein was identified in the presence of rAAV2/8-hAGA at 6, 12, and 24 weeks after treatment. α-Gal A activity was significantly higher in the mice treated with rAAV2/8-hAGA than in Fabry mice that received ERT. Along with higher α-Gal A activity in the kidney of the Fabry mice treated with gene therapy, immunohistochemical studies showed more α-Gal A expression in the proximal tubules and glomerulus, and less Gb3 deposition in Fabry mice treated with this gene therapy than in mice given ERT. The α-gal A gene transfer significantly reduced the accumulation of Gb3 in the tubules and podocytes of the kidney. Electron microscopic analysis of the kidneys of Fabry mice also showed that gene therapy was more effective than ERT.</p> <p>Conclusions</p> <p>The rAAV2/8-hAGA mediated α-Gal A gene therapy provided improved efficiency over ERT in the Fabry disease mouse model. Furthermore, rAAV2/8-hAGA-mediated expression showed a greater effect in the kidney than ERT.</p

Characterization and source of fluorescent dissolved organic matter in the Western Arctic Ocean: new insights from the 2019 summer study

Increase in river discharge and seasonal primary production and decline in sea ice coverage in the Arctic Ocean in summer can significantly affect the distribution and composition of dissolved organic matter (DOM). This study aimed to enhance the current available knowledge about the impacts of environmental changes on the characteristics of DOM in the rapidly changing Arctic Ocean. Seawater samples were collected from the western Arctic Ocean during the summer of 2019 and analyzed for fluorescent DOM (FDOM), dissolved organic carbon (DOC), and stable oxygen isotope (δ18O) content in conjunction with biophysical properties. We identified two humic-like (C1 and C2) and one protein-like (C3) components using fluorescence excitation-emission matrix coupled with parallel factor (EEM–PARAFAC) analysis. Remarkably high intensities of humic-like FDOM were found in the upper halocline layer (32 &lt; salinity &lt; 33.5 psu, at depths between 50–200 m) with high inorganic nutrient concentrations and low N* values, indicating that the humic-like FDOM was supplied from the shelf sediment. Furthermore, shoaling of the upper halocline layer brought high levels of humic-like FDOM to the euphotic zone, resulting in an increased probability of photodegradation of humic-like FDOM due to exposure to solar radiation in the surface layer. Tryptophan-like FDOM was positively correlated with river water fraction (friver) and riverine DOC but not with chlorophyll-a (Chl-a) and heterotrophic bacterial abundance, indicating river discharge as a potential additional source of tryptophan-like FDOM. The correlation coefficients between tryptophan-like FDOM and river water parameters (friver and riverine DOC) differed across the Chukchi Sea, Chukchi Borderland, and East Siberian Sea, implying that the influence of river discharge on tryptophan-like FDOM is region-dependent. An increase in river discharge in future might lead to a greater supply of tryptophan-like FDOM, impacting the dynamics of DOM cycling in the western Arctic Ocean

Acute Appendicitis in Henoch-Schönlein Purpura : A Case Report

Common complications of Henoch-Schönlein purpura (HSP) that lead to surgical intervention include intussusception, perforation, necrosis, and massive gastrointestinal bleeding. Acute appendicitis is rarely seen as a complication of HSP. A seven-year-old boy was admitted for arthralgia, abdominal pain, hematochezia, melena, and purpuric rash on the lower extremities. On admission day abdominal ultrasonography was normal, but on day 5, he became pyrexial and developed right iliac fossa pain and tenderness with guarding. Ultrasonography showed distended appendix surrounded by hyperechoic inflamed fat. On exploration an acutely inflamed, necrotic appendix was removed and grossly there was an appendiceal perforation in the appendiceal tip. Microscopically some of the small blood vessels in the submucosa showed fibrinoid necrosis with neutrophilic infiltrations. The authors report the case of a child who developed acute perforative appendicitis requiring appendectomy while on treatment for HSP

Concurrent smoking and alcohol consumers had higher triglyceride glucose indices than either only smokers or alcohol consumers: a cross-sectional study in Korea

Background The triglyceride glucose (TyG) index is a noninsulin-based marker for insulin resistance (IR) in general practice. Although smoking and heavy drinking have been regarded as major risk factors for various chronic diseases, there is limited evidence regarding the combined effects of smoking and alcohol consumption on IR. This study aimed to investigate the relationship between the TyG index and smoking and alcohol consumption using two Korean population-based datasets. Methods This study included 10,568 adults in the Korean National Health and Nutrition Examination Survey (KNHANES) and 9586 adults in the Korean Initiatives on Coronary Artery Calcification (KOICA) registry datasets. Multivariate logistic analysis was conducted to explore the relationship between smoking and alcohol consumption and the TyG index. To assess the predictive value of smoking and alcohol consumption on high TyG index, the area under the curve (AUC) were compared and net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses were derived. Results The combined effect of smoking and alcohol consumption was an independent risk factor of a higher TyG index in the KNHANES (adjusted odds ratio: 4.33, P < .001) and KOICA (adjusted odds ratio: 1.94, P < .001) datasets. Adding smoking and alcohol consumption to the multivariate logistic models improved the model performance for the TyG index in the KNHANES (AUC: from 0.817 to 0.829, P < .001; NRI: 0.040, P < .001; IDI: 0.017, P < .001) and KOICA (AUC: from 0.822 to 0.826, P < .001; NRI: 0.025, P = .006; IDI: 0.005, P < .001) datasets. Conclusions Smoking and alcohol consumption were independently associated with the TyG index. Concurrent smokers and alcohol consumers were more likely to have a TyG index that was ≥8.8 and higher than the TyG indices of non-users and those who exclusively consumed alcohol or smoking tobacco.This work was supported by the Technology Innovation Program (20002781, A Platform for Prediction and Management of Health Risk Based on Personal Big Data and Lifelogging) funded by the Ministry of Trade, Industry and Energy (MOTIE, South Korea) to JW Lee, and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) Baek et al. Lipids in Health and Disease (2021) 20:49 Page 9 of 11 (NRF-2019R1A2C1010043) to H Lee. Additionally, this work was supported by Institute for Information and Communications Technology Promotion (IITP) grant funded by the Korean government (MSIT) (2019-31-1293), for autonomous digital companion framework and application to HJ Chan

Protective Effect of Recombinant Adeno-Associated Virus 2/8-Mediated Gene Therapy from the Maternal Hyperphenylalaninemia in Offsprings of a Mouse Model of Phenylketonuria

Phenylketonuria (PKU) is an autosomal recessively inherited metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine leads to severe mental and psychomotor retardation, and the fetus of an uncontrolled pregnant female patient presents with maternal PKU syndrome. We have reported previously on the cognitive outcome of biochemical and phenotypic reversal of PKU in a mouse model, Pahenu2, by the AAV serotype 2-mediated gene delivery of a human PAH transgene. However, the therapeutic efficacy had been limited to only male PKU mice. In this study, we generated a pseudotyped recombinant AAV2/8-hPAH vector and infused it into female PKU mice through the hepatic portal vein or tail vein. Two weeks after injection, complete fur color change to black was observed in female PKU, as in males. The PAH activity in the liver increased to 65-70% of the wild-type activity in female PKU mice and to 90% in male PKU mice. Plasma phenylalanine concentration in female PKU mice decreased to the normal value. In addition, the offsprings of the treated female PKU mice can rescue from the harmful effect of maternal hyperphenylalaninemia. These results indicate that recombinant AAV2/8-mediated gene therapy is a potential therapeutic strategy for PKU