AAV8-Mediated Hepatic Expression of Acid Sphingomyelinase Corrects the Metabolic Defect in the Visceral Organs of a Mouse Model of Niemann|[ndash]|Pick Disease

doi:doi:10.1016/j.ymthe.2005.03.011

Molecular Therapy (2005) 12, 431–440; doi: 10.1016/j.ymthe.2005.03.011

AAV8-Mediated Hepatic Expression of Acid Sphingomyelinase Corrects the Metabolic Defect in the Visceral Organs of a Mouse Model of Niemann–Pick Disease

Christine M. Barbon¹, Robin J. Ziegler¹, Chester Li¹, Donna Armentano¹, Maribeth Cherry¹, Robert J. Desnick², Edward H. Schuchman² and Seng H. Cheng¹

¹Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701-9322, USA
²Mount Sinai School of Medicine, New York, NY 10029, USA

Correspondence: Seng H. Cheng, Fax: +1 (508) 872 4091. E-mail: seng.cheng@genzyme.com

Received 8 January 2005; Accepted 19 March 2005.

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Abstract

Acid sphingomyelinase deficiency is a lysosomal storage disorder in which the defective lysosomal hydrolase fails to degrade sphingomyelin. The resulting accumulation of substrate in the lysosomes of histiocytic cells leads to hepatosplenomegaly and severe pulmonary inflammation. Administration of a recombinant AAV1 vector encoding human acid sphingomyelinase to acid sphingomyelinase knockout (ASMKO) mice effectively reduced the accumulated substrate in all of the affected visceral organs. However, more complete and rapid clearance of sphingomyelin was observed when an AAV8-based serotype vector was used in lieu of AAV1. Importantly, AAV8-mediated hepatic expression of higher and sustained levels of the enzyme also corrected the abnormal cellularity, cell differentials, and levels of the chemokine MIP-1 alpha in the bronchoalveolar lavage fluids of the ASMKO mice. Treatment also reversed the morphological aberrations associated with the alveolar macrophages of ASMKO mice and restored their phagocytic activity. No antibodies to the expressed enzyme were detected when the viral vectors were used in conjunction with a transcription cassette harboring a liver-restricted enhancer/promoter. Together, these data support the continued development of AAV8-mediated hepatic gene transfer as an approach to treat the visceral manifestations observed in individuals with acid sphingomyelinase deficiency.