Lentivirus-mediated gene therapy for Fabry disease: 5-year End-of-Study results from the Canadian FACTs trial.

Background: Fabry disease is an X-linked lysosomal storage disorder due to a deficiency of α-galactosidase A (α-gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α-gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs). Overexpression of α-gal A leads to secretion of the hydrolase; which can be taken up and used by uncorrected bystander cells.

Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease.

The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease-a rare X-linked lysosomal storage disorder caused by gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gene therapy trials, we conducted a comprehensive DNA insertion site analysis of peripheral blood samples from the five patients in our gene therapy trial. We found that patients had a polyclonal integration site spectrum and did not find evidence of a dominant clone in any patient.

Lentivirus-mediated gene therapy for Fabry disease.

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A).

Distribution of heparan sulfate and dermatan sulfate in mucopolysaccharidosis type II mouse tissues pre- and post-enzyme-replacement therapy determined by UPLC-MS/MS.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by a deficiency of the iduronate-2-sulfatase enzyme leading to the accumulation of heparan sulfate (HS) and dermatan sulfate (DS) in organs and biological fluids. enzyme-replacement therapy is available for affected patients. A 6-min UPLC-MS/MS method was developed/validated for HS and DS quantification in mouse tissues and biological fluids with high accuracy and precision.

Analysis of globotriaosylceramide (Gb) isoforms/analogs in unfractionated leukocytes, B lymphocytes and monocytes from Fabry patients using ultra-high performance liquid chromatography/tandem mass spectrometry.

Fabry disease is an X-linked lysosomal storage disorder with marked variability in the phenotype and genotype. Glycosphingolipids such as globotriaosylceramide (Gb) isoforms/analogs, globotriaosylsphingosine (lyso-Gb) and analogs, and galabiosylceramide (Ga) isoforms/analogs may accumulate in biological fluids and different organs. The aims of this study were to: 1) develop/validate a novel UHPLC-MS/MS method for relative quantitation of Gb in leukocytes (unfractionated white blood cells), B lymphocytes and monocytes; 2) evaluate these biomarkers in a cohort of Fabry patients and healthy controls; and 3) assess correlations between these biomarkers, treatment and genotype.

Glycosphingolipid storage in Fabry mice extends beyond globotriaosylceramide and is affected by ABCB1 depletion.

Aim: Fabry disease is caused by α-galactosidase A deficiency leading to accumulation of globotriaosylceramide (Gb) in tissues. Clinical manifestations do not appear to correlate with total Gb levels. Studies examining tissue distribution of specific acyl chain species of Gb and upstream glycosphingolipids are lacking.

High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis.

Background: Selenium (Se) is an essential trace element with antioxidant, anti-inflammatory, and immunomodulatory effects. So far, several randomized clinical trials (RCTs) have demonstrated that parenteral Se may improve clinical outcomes in intensive care unit (ICU) patients. Since publication of our previous systematic review and meta-analysis on antioxidants in the ICU, reports of several trials have been published, including the largest RCT on Se therapy.

UPLC-MS/MS detection of disaccharides derived from glycosaminoglycans as biomarkers of mucopolysaccharidoses.

Mucopolysaccharidoses (MPSs) are a group of disorders resulting from primary defects in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Depending on the specific enzyme defect, the catabolism of one or more GAGs is blocked leading to accumulation in tissues and biological fluids. GAG measurements are important for high-risk screening, diagnosis, monitoring treatment efficacy, and patient follow up.

[Fish oil containing lipid emulsions in critically ill patients: Critical analysis and future perspectives].

Third-generation lipid emulsions (LE) are soybean oil sparing strategies with immunomodulatory and antiinflammatory effects. Current evidence supporting the use of intravenous (i.v) fish oil (FO) LE in critically ill patients requiring parenteral nutrition or receiving enteral nutrition (pharmaconutrient strategy) mainly derives from small phase ii clinical trials in heterogenous intensive care unit patient's population.