Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse

• DOI: 10.1073/pnas.0703509104
• Publication Date: 2007-05-22T22:08:20Z
• Authors: Marco A. Passini; Jie Bu; Jonathan A. Fidler; Robin J. Ziegler; Joseph W. Foley; James C. Dodge; Wendy W. Yang; Jennifer Clarke; Tatyana V. Taksir; Denise A. Griffiths; Michael A. Zhao; Catherine R. O'Ri...; Edward H. Schuchman; Lamya S. Shihabuddin; Seng H. Cheng
• Keywords: Systemic administration; Niemann–Pick disease; Acid sphingomyelinase; Combination therapy

Niemann-Pick disease (NPD) is caused by the loss of acid sphingomyelinase (ASM) activity, which results in widespread accumulation undegraded lipids cells viscera and CNS. In this study, we tested effect combination brain systemic injections recombinant adeno-associated viral vectors encoding human ASM (hASM) a mouse model NPD. Animals treated therapy exhibited high levels hASM brain, resulted near-complete correction storage throughout body. This global reversal pathology translated to normal weight gain superior recovery motor cognitive functions compared animals either or injection alone. Furthermore, group did not generate antibodies hASM, demonstrating first application systemic-mediated tolerization improve efficacy injections. All survived good health an investigator-selected 54 weeks, whereas median lifespans systemic-alone, brain-alone, untreated knockout groups were 47, 48, 34 respectively. These data demonstrate that promising therapeutic modality for treating NPD suggest potential strategy indications cause both visceral CNS pathologies.