title: Pulmonary delivery of recombinant acid sphingomyelinase improves clearance of lysosomal sphingomyelin from the lungs of a murine model of Niemann-Pick disease.
abstract: Systemic administration of recombinant acid sphingomyelinase (rhASM) into ASM deficient mice (ASMKO) results in hydrolysis of the abnormal storage of sphingomyelin in lysosomes of the liver, spleen and lung. However, the efficiency with which the substrate is cleared from the lung, particularly the alveolar macrophages, appears to be lower than from the other visceral tissues. To determine if delivery of rhASM into the air spaces of the lung could enhance clearance of pulmonary sphingomyelin, enzyme was administered to ASMKO mice by intranasal instillation. Treatment resulted in a significant and dose-dependent reduction in sphingomyelin levels in the lung. Concomitant with this reduction in substrate levels was a decrease in the amounts of the pro-inflammatory cytokine, MIP-1alpha, in the bronchoalveolar lavage fluids and an improvement in lung pathology. Maximal reduction of lung sphingomyelin levels was observed at 7 days post-treatment. However, reaccumulation of the substrate was noted starting at day 14 suggesting that repeated treatments will be necessary to effect a sustained reduction in sphingomyelin levels. In addition to reducing the storage abnormality in the lung, intranasal delivery of rhASM also resulted in clearance of the substrate from the liver and spleen. Hence, pulmonary administration of rhASM may represent an alternative route of delivery to address the visceral pathology associated with ASM deficiency.
authors.affiliation: Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701-9322, USA. robin.ziegler@genzyme.com
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Ziegler
authors.forename: Claire
authors.initials: C
authors.lastname: Brown
authors.forename: Christine M
authors.initials: CM
authors.lastname: Barbon
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: D'Angona
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.forename: Laura
authors.initials: L
authors.lastname: Andrews
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.forename: John M
authors.initials: JM
authors.lastname: McPherson
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Karey
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009542:Niemann-Pick Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D013108:Sphingomyelin Phosphodiesterase / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*; D013109:Sphingomyelins / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D011994:Recombinant Proteins; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase