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Titolo:
Enzyme therapy for lysosomal acid lipase deficiency in the mouse
Autore:
Du, H; Schiavi, S; Levine, M; Mishra, J; Heur, M; Grabowski, GA;
Indirizzi:
Childrens Hosp Res Fdn, Div Human Genet, Cincinnati, OH 45229 USA Childrens Hosp Res Fdn Cincinnati OH USA 45229 , Cincinnati, OH 45229 USA Genzyme Corp, Cambridge, MA USA Genzyme Corp Cambridge MA USAGenzyme Corp, Cambridge, MA USA
Titolo Testata:
HUMAN MOLECULAR GENETICS
fascicolo: 16, volume: 10, anno: 2001,
pagine: 1639 - 1648
SICI:
0964-6906(20010801)10:16<1639:ETFLAL>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECOMBINANT BETA-GLUCURONIDASE; MUCOPOLYSACCHARIDOSIS TYPE-VII; MACROPHAGE MANNOSE RECEPTOR; CHOLESTERYL ESTER; GAUCHER-DISEASE; IDENTIFICATION; REPLACEMENT; PROTEIN; STORAGE; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Grabowski, GA Childrens Hosp Res Fdn, Div Human Genet, 3333 Burnet Ave, Cincinnati, OH 45229 USA Childrens Hosp Res Fdn 3333 Burnet Ave Cincinnati OHUSA 45229
Citazione:
H. Du et al., "Enzyme therapy for lysosomal acid lipase deficiency in the mouse", HUM MOL GEN, 10(16), 2001, pp. 1639-1648

Abstract

Lysosomal acid lipase (LAL) is the critical enzyme for the hydrolysis of the triglycerides (TG) and cholesteryl esters (CE) delivered to lysosomes. Its deficiency produces two human phenotypes, Wolman disease (WD) and cholesteryl ester storage disease (CESD). A targeted disruption of the LAL locus produced a null (lal(-/-)) mouse model that mimics human WD/CESD. The potential for enzyme therapy was tested using mannose terminated human LAL expressed in Pichia pastoris (phLAL), purified, and administered by tall vein injections,to lal(-/-) mice. Mannose receptor (MR)-dependent uptake and lysosomal targeting of phLAL were evidenced ex vivo using competitive assays with MR-positive J774E cells, a murine monocyte/macrophage line, immunofluorescence and western blots. Following (bolus) IV injection, phLAL was detectedin Kupffer cells, lung macrophages and intestinal macrophages in lal(-/-) mice. Two-month-old lal(-/-) mice received phl-AL (1.5 U/dose) or saline injections once every 3 days for 30 days (10 doses). The treated lal(-/-) mice showed nearly complete resolution of hepatic yellow coloration; hepatic weight decreased by similar to 36% compared to PBS-treated lal(-/-) mice. Histologic analyses of numerous tissues from phl-AL-treated mice showed reductions in macrophage lipid storage. TG and cholesterol levels decreased by similar to 50% in liver, 69% in spleen and 50% in small intestine. These studies provide feasibility for LAL enzyme therapy in human WD and CESD.

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Documento generato il 13/12/17 alle ore 23:32:49