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

Abstract

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.acid sphingomyelinase ͉ adeno-associated virus ͉ immunotolerization ͉ lysosomal storage disease ͉ neurodegeneraton

Safety Study of Adeno-Associated Virus Serotype 2-Mediated Human Acid Sphingomyelinase Expression in the Nonhuman Primate Brain

“…The ASM knockout mice develop neurological deficits due to massive loss of Purkinje cells in the cerebellum (Otterbach and Stoffel, 1995), thus mimicking the phenotype of the human disease (Kitagawa, 1987;Otterbach and Stoffel, 1995;Zhou et al, 1995). The efficacy studies most relevant to the present work, however, are those in which ASM knockout mice received AAV-hASM (Dodge et al, 2005;Passini et al, 2005Passini et al, , 2007. In particular, Passini and colleagues (2005) showed that treatment with AAV2-hASM (1) corrected the distended lysosome pathology (2), restored normal cholesterol levels in brain (secondary substrate), and that AAV particles (3) can undergo axonal transport to distal areas of brains, despite the fact that projection neurons are sick at the time of injection (i.e., diseasecompromised neurons support transport of AAV).…”

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

“…Several strategies are currently being tested for the treatment of MPSs and other lysosomal storage disorders, including enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy with unmodified [8–11] or modified enzymes [12,13]. Unfortunately, these approaches have inherent challenges because enzymes provided by HSCT or ERT have only limited ability to transit through the blood-brain barrier [14,15].…”

Gene therapy for the neurological manifestations in lysosomal storage disorders

“…For example, the underlying molecular bases for most of these monogenic disorders are well understood. Importantly, genetic correction of a small subset of neural cells may suffi ce to correct large regions of the CNS by virtue of the ability of the enzymes to diffuse and affect crosscorrection of adjacent and distal cells (33)(34)(35)(36)(37)(38). Diffusion of the enzymes may occur via the ventricular system or may be facilitated by axonal transport from the site of production to distal sites ( 39 ).…”