Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation

Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcome

Initial Evaluation of the Effects of Aerosolized Florida Red Tide Toxins (Brevetoxins) in Persons with Asthma

Florida red tides annually occur in the Gulf of Mexico, resulting from blooms of the marine dinoflagellate Karenia brevis. K. brevis produces highly potent natural polyether toxins, known as brevetoxins, that activate voltage-sensitive sodium channels. In experimental animals, brevetoxins cause significant bronchoconstriction. A study of persons who visited the beach recreationally found a significant increase in self-reported respiratory symptoms after exposure to aerosolized Florida red tides. Anecdotal reports indicate that persons with underlying respiratory diseases may be particularly susceptible to adverse health effects from these aerosolized toxins. Fifty-nine persons with physician-diagnosed asthma were evaluated for 1 hr before and after going to the beach on days with and without Florida red tide. Study participants were evaluated with a brief symptom questionnaire, nose and throat swabs, and spirometry approved by the National Institute for Occupational Safety and Health. Environmental monitoring, water and air sampling (i.e., K. brevis, brevetoxins, and particulate size distribution), and personal monitoring (for toxins) were performed. Brevetoxin concentrations were measured by liquid chromatography mass spectrometry, high-performance liquid chromatography, and a newly developed brevetoxin enzyme-linked immunosorbent assay. Participants were significantly more likely to report respiratory symptoms after Florida red tide exposure. Participants demonstrated small but statistically significant decreases in forced expiratory volume in 1 sec, forced expiratory flow between 25 and 75%, and peak expiratory flow after exposure, particularly those regularly using asthma medications. Similar evaluation during nonexposure periods did not significantly differ. This is the first study to show objectively measurable adverse health effects from exposure to aerosolized Florida red tide toxins in persons with asthma. Future studies will examine the possible chronic effects of these toxins among persons with asthma and other chronic respiratory impairment

Retinal Degeneration Progression Changes Lentiviral Vector Cell Targeting in the Retina

In normal mice, the lentiviral vector (LV) is very efficient to target the RPE cells, but transduces retinal neurons well only during development. In the present study, the tropism of LV has been investigated in the degenerating retina of mice, knowing that the retina structure changes during degeneration. We postulated that the viral transduction would be increased by the alteration of the outer limiting membrane (OLM). Two different LV pseudotypes were tested using the VSVG and the Mokola envelopes, as well as two animal models of retinal degeneration: light-damaged Balb-C and Rhodopsin knockout (Rho-/-) mice. After light damage, the OLM is altered and no significant increase of the number of transduced photoreceptors can be obtained with a LV-VSVG-Rhop-GFP vector. In the Rho-/- mice, an alteration of the OLM was also observed, but the possibility of transducing photoreceptors was decreased, probably by ongoing gliosis. The use of a ubiquitous promoter allows better photoreceptor transduction, suggesting that photoreceptor-specific promoter activity changes during late stages of photoreceptor degeneration. However, the number of targeted photoreceptors remains low. In contrast, LV pseudotyped with the Mokola envelope allows a wide dispersion of the vector into the retina (corresponding to the injection bleb) with preferential targeting of Müller cells, a situation which does not occur in the wild-type retina. Mokola-pseudotyped lentiviral vectors may serve to engineer these glial cells to deliver secreted therapeutic factors to a diseased area of the retina

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Paradoxical whole genome DNA methylation dynamics of 5’aza-deoxycytidine in chronic low-dose exposure in mice

Decitabine (5-aza-2ʹdeoxycytidine; DAC) is a DNA methyltransferase inhibitor used to hypomethylate the epigenome. Current dosing regimens of DAC for use in mice vary widely and their hypomethylating ability has not been robustly characterized, despite reliable results of hypomethylation of the epigenome with cell lines in vitro and tissue specificity in vivo. We investigated the effects on the DNA methylome and gene expression within mice exposed to chronic low doses of DAC ranging from 0 to 0.35 mg/kg over a period of 7 weeks without causing toxicity. Our dose paradigm resulted in no cytotoxic effects within target tissues, although testes weight and sperm concentration significantly reduced as dose increased (p-value <0.05). By whole genome bisulphite sequencing (WGBS), we identify tissue and dose-specific differentially methylated CpGs (DMCs) and regions (DMRs) in testes and liver. Testes methylation is more sensitive to DAC exposure when compared to liver, cortex, and hippocampus. Gene expression was dysregulated in testes and liver, targeting non-specific pathways as dose increases. Together our data suggest DNA methylation and gene expression are disrupted by in vivo DAC treatment in a non-uniform manner contrary to expectations, and that no dose level or regimen is sufficient to cause systemic hypomethylation in whole mice

Environmental exposures to Florida red tides: Effects on emergency room respiratory diagnoses admissions

Human exposure to Florida red tides formed by Karenia brevis, occurs from eating contaminated shellfish and inhaling aerosolized brevetoxins. Recent studies have documented acute symptom changes and pulmonary function responses after inhalation of the toxic aerosols, particularly among asthmatics. These findings suggest that there are increases in medical care facility visits for respiratory complaints and for exacerbations of underlying respiratory diseases associated with the occurrence of Florida red tides. This study examined whether the presence of a Florida red tide affected the rates of admission with a respiratory diagnosis to a hospital emergency room in Sarasota, FL. The rate of respiratory diagnoses admissions were compared for a 3-month time period when there was an onshore red tide in 2001 (red tide period) and during the same 3-month period in 2002 when no red tide bloom occurred (non-red tide period). There was no significant increase in the total number of respiratory admissions between the two time periods. However, there was a 19% increase in the rate of pneumonia cases diagnosed during the red tide period compared with the non-red tide period. We categorized home residence zip codes as coastal (within 1.6 km from the shore) or inland (>1.6 km from shore). Compared with the non-red tide period, the coastal residents had a significantly higher (54%) rate of respiratory diagnoses admissions than during the red tide period. We then divided the diagnoses into subcategories (i.e. pneumonia, bronchitis, asthma, and upper airway disease). When compared with the non-red tide period, the coastal zip codes had increases in the rates of admission of each of the subcategories during the red tide period (i.e. 31, 56, 44, and 64%, respectively). This increase was not observed seen in the inland zip codes. These results suggest that the healthcare community has a significant burden from patients, particularly those who live along the coast, needing emergency medical care for both acute and potentially chronic respiratory illnesses during red tide blooms

Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry

These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease. Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 months before starting enzyme replacement therapy were included. Most men (86 of 121, 71%) had more rapid loss of kidney function than the normal adult population (loss of eGFR > -1 ml/min per 1.73 m(2) per year), whereas fewer women (133 of 341, 39%) had rapid loss of kidney function. Patients with rapid progression had significantly higher mean averaged urinary protein to urinary creatinine ratios (UP/Cr) than patients with slower progression (1.5 versus 0.2 for men; 1.4 versus 0.5 for women; P 1.5 (mean eGFR slope, -5.6 ml/min per 1.73 m(2) per year; n = 30). eGFR slope declined more slowly in women, with the steepest declines observed in women with UP/Cr > 1.2 (mean eGFR slope, -1.3 ml/min per 1.73 m(2) per year; n = 85). Regression models of eGFR slope indicated that UP/Cr is the most important indicator of renal disease progression in adult Fabry patients. In women, lower baseline eGFR and age were also associated with renal disease progression. Women who had clinical events had more rapid loss of kidney function. Urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry diseas