Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse.
Niemann-Pick disease (NPD) is caused by the loss of acid sphingomyelinase (ASM) activity, which results in widespread accumulation of undegraded lipids in cells of the viscera and CNS. In this study, we tested the effect of combination brain and systemic injections of recombinant adeno-associated viral vectors encoding human ASM (hASM) in a mouse model of NPD. Animals treated by combination therapy exhibited high levels of hASM in the viscera and brain, which resulted in near-complete correction of storage throughout the body. This global reversal of pathology translated to normal weight gain and superior recovery of motor and cognitive functions compared to animals treated by either brain or systemic injection alone. Furthermore, animals in the combination group did not generate antibodies to hASM, demonstrating the first application of systemic-mediated tolerization to improve the efficacy of brain injections. All of the animals treated by combination therapy survived in good health to an investigator-selected 54 weeks, whereas the median lifespans of the systemic-alone, brain-alone, or untreated ASM knockout groups were 47, 48, and 34 weeks, respectively. These data demonstrate that combination therapy is a promising therapeutic modality for treating NPD and suggest a potential strategy for treating disease indications that cause both visceral and CNS pathologies.
Passini
Marco A
MA
Genzyme Corporation, Framingham, MA 01701, USA. marco.passini@genzyme.com
Bu
Jie
J
Fidler
Jonathan A
JA
Ziegler
Robin J
RJ
Foley
Joseph W
JW
Dodge
James C
JC
Yang
Wendy W
WW
Clarke
Jennifer
J
Taksir
Tatyana V
TV
Griffiths
Denise A
DA
Zhao
Michael A
MA
O'Riordan
Catherine R
CR
Schuchman
Edward H
EH
Shihabuddin
Lamya S
LS
Cheng
Seng H
SH
D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D000229:Dependovirus / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009542:Niemann-Pick Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D015996:Survival Rate
D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase