Cardiac involvement was present early in more than a half of the patients identified as having mucopolysaccharidosis, and generally progressed, being more frequent and severe in the first and second types of the disease. Longer follow-up is needed to demonstrate any significant improvement induced by new therapies.

Airway inflammation frequently found in congenital and mice efficiently transfected primarily the lungs and to a acquired lung diseases may interfere with gene delivery by lesser extent, heart, spleen, kidney and liver. The other direct administration through either instillation or aerosol.vectors mediated lower to undetectable levels of luciferase Systemic delivery by the intravenous administration repexpression in the lungs, with DOTAP Ͼ GL67/DOPE Ͼ PEI resents an alternative route of delivery that might bypass 25K Ͼ DOTMA/DOPE. A double injection protocol with a this barrier. A nonviral approach for transfecting various 15-min interval between the two doses of DOTAP/DNA airway-derived cell lines in vitro showed that cationic polycomplexes was investigated and showed a relevant role of mers (PEI 22K and 25K) and lipids (DOTAP, GL-67/DOPE) the first injection in transfecting the lungs. A two log are able to transfect with high efficiency the reporter genes increase in luciferase expression was obtained either when firefly luciferase and E. coli lacZ. Notably, two properties the two doses were comprised of luciferase plasmid or predicted that cationic vectors would be useful for a syswhen an irrelevant plasmid was used in the first injection. temic gene delivery approach to the lung: (1) transfectionThe double injection of luciferase/PEI 22K complexes was not inhibited or increased when cells were incubated determined higher transgene levels than a single dose, but with cationic lipids or polymers in the presence of serum; a clear difference using an irrelevant plasmid as first dose and (2) cationic vectors protected plasmid DNA from was not observed. Using lacZ as a reporter gene, it was DNase degradation. A single injection of DNA complexed shown that only cells in the alveolar region, including type II to the cationic polymer PEI 22K into the tail vein of adult penumocytes, stained positively for the transgene product.

No abstract

MPS VI (mucopolysaccharidosis type VI) is a lysosomal storage disease in which deficient activity of the enzyme N-acetylgalactosamine 4-sulfatase [ASB (arylsulfatase B)] impairs the stepwise degradation of the GAG (glycosaminoglycan) dermatan sulfate. Clinical studies of ERT (enzyme replacement therapy) by using rhASB (recombinant human ASB) have been reported with promising results. The release of GAG into the urine is currently used as a biomarker of disease, reflecting in some cases disease severity and in all cases therapeutic responsiveness. Using RNA studies in four Italian patients undergoing ERT, we observed that TNFalpha (tumour necrosis factor alpha) might be a biomarker for MPS VI responsive to therapy. In addition to its role as a potential biomarker, TNFalpha expression could provide insights into the possible pathophysiological mechanisms underlying the mucopolysaccharidoses.

Mucopolysaccharidosis (MPS) describes any inherited lysosomal storage disorder resulting from an inability to catabolize glycosaminoglycans. MPS III (or Sanfilippo syndrome) is an autosomal recessive disease caused by a failure to degrade heparan sulphate. There are four subtypes of MPS III, each categorized by a deficiency in a specific enzyme involved in the heparan sulphate degradation pathway. The genes mutated in three of these (MPS IIIA, MPS IIIB, and MPS IIID) have been cloned for some time. However, only very recently has the gene for MPS IIIC (heparin acetyl CoA: alpha-glucosaminide N-acetyltransferase, or HGSNAT) been identified. Its product (previously termed transmembrane protein 76, or TMEM76) has little sequence similarity to other proteins of known function, although it is well conserved among all species. In this study, a group of MPS IIIC patients, who are mainly of Italian origin, have been clinically characterized. Furthermore, mutational analysis of the HGSNAT gene in these patients resulted in the identification of nine alleles, of which eight are novel. Three splice-site mutations, three frameshift deletions resulting in premature stop codons, one nonsense mutation, and two missense mutations were identified. The latter are of particular interest as they are located in regions which are predicted to be of functional significance. This research will aid in determining the molecular basis of HGSNAT protein function, and the mechanisms underlying MPS IIIC.