Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus

Watson, G. L.; Sayles, JN; Chen, C; Elliger, SS; Elliger, CA; Raju, NR; Kurtzman, Gary J.; Podsakoff, Gregory M.

doi:10.1038/sj.gt.3300775

Cited by 82 publications

(58 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies have shown that AAV-mediated gene transfer corrects neuropathology and, to a lesser extent, behavioral deficits in mouse models of neurometabolic disease (21)(22)(23)(24)(25)(26)(27). However, experiments in various lysosomal storage disease mouse models (e.g., mucopolysaccharidosis VII, infantile neuronal ceroid lipofuscinosis, and Sanfilippo type IIIB disease) have been primarily restricted to AAV serotypes 1 and 2 to mediate gene transfer in the brain.…”

Section: Discussionmentioning

confidence: 99%

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Dodge

Clarke

Song

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Niemann-Pick type A disease is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously we showed that storage pathology in the ASM knockout (ASMKO) mouse brain can be corrected by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer. The present experiment compared the relative therapeutic efficacy of different recombinant AAV serotype vectors (1, 2, 5, 7, and 8) using histological, biochemical, and behavioral endpoints. In addition, we evaluated the use of the deep cerebellar nuclei (DCN) as a site for injection to facilitate global distribution of the viral vector and enzyme. Seven-week-old ASM knockout mice were injected within the DCN with different AAV serotype vectors encoding human ASM (hASM) and then killed at either 14 or 20 weeks of age. Results showed that AAV1 was superior to serotypes 2, 5, 7, and 8 in its relative ability to express hASM, alleviate storage accumulation, and correct behavioral deficits. Expression of hASM was found not only within the DCN, but also throughout the cerebellum, brainstem, midbrain, and spinal cord. This finding demonstrates that targeting the DCN is an effective approach for achieving widespread enzyme distribution throughout the CNS. Our results support the continued development of AAV based vectors for gene therapy of the CNS manifestations in Niemann-Pick type A disease.axonal transport ͉ deep cerebellar nuclei ͉ gene therapy ͉ lysosomal storage diseases ͉ adeno-associated virus N iemann-Pick type A disease (NPA) is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Loss of ASM activity results in lysosomal sphingomyelin (SPM) accumulation, secondary metabolic defects such as aberrant cholesterol metabolism, and subsequently the loss of cellular function in various organ systems including the central nervous system (CNS) (1, 2). Previously, we demonstrated that intracerebral delivery of adeno-associated virus serotype-2 encoding human ASM (AAV2-hASM) is effective in correcting lysosomal storage pathology in ASM knockout (ASMKO) mice (3). Interestingly, correction of lysosomal storage pathology not only occurred at the injection site (i.e., hippocampus), but also in regions (e.g., entorhinal cortex) that send and͞or receive input from the injection site. This finding, in accordance with previous work (4), demonstrated that neuronal circuits can be used to achieve AAV vector and protein distribution via axonal transport to regions that are proximal or distal to the injection site.Despite our initial success with AAV2, investigation of the relative therapeutic efficacy of additional serotypes is warranted. Serotype-dependent variations in cellular tropism, rates of diffusion, and transduction efficiencies may translate into disparate levels of therapeutic efficacy (5, 6). Furthermore, we wish to show that AAV-mediated hASM expression prevents disease initiated neurodegeneration (i.e., Purkinje cell loss) and disturbances in motor function in ASMKO mice (7, §).To examine...

show abstract

Section: Discussionmentioning

confidence: 99%

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Dodge

Clarke

Song

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…They show widespread storage of GAGs in lysosomes of visceral organs, skeleton, and brain. The murine model of MPS VII has been widely used for evaluating the effectiveness of bone marrow transplantation (10)(11)(12)(13)(14), enzyme replacement (15)(16)(17)(18)(19)(20)(21)(22), and gene therapy with retroviral (23)(24)(25)(26)(27)(28), adenoviral (29 -33), and adenoassociated viral vectors (34)(35)(36)(37)(38)(39).…”

mentioning

confidence: 99%

Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

Sly

Vogler

Grubb

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of ␤-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gus mps/mps ) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human ␤-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gus mps/mps ) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gus mps/mps ) mouse. However, they are now tolerant to immune challenge with human ␤-glucuronidase. This ''tolerant MPS VII mouse model'' should be useful for preclinical trials evaluating the effectiveness of enzyme and͞or gene therapy with the human gene products likely to be administered to human patients with MPS VII.

show abstract

“…The exciting potential of AAV-mediated gene delivery to meet this challenge is substantiated by data generated in over 40 studies in animal models involving at least 15 different LSD phenotypes. The most extensively investigated phenotypes are GSD II [40][41][42][43][44][45][46] and MPS VII [47][48][49][50][51][52][53][54] and distillation of data obtained for these conditions provides representative insights across the spectrum of LSDs.…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

“…Initial studies of phenotype correction in the mouse using AAV vectors, performed in the late 1990s, focused on systemic delivery of enzyme by either direct intramuscular or intravenous injection. 47,48 While intramuscular injection resulted in high localized enzyme production, cross-correction of other tissues was limited, probably as a consequence of inadequate local secretion and distal tissue uptake. Intravenous delivery resulted in measurable enzyme levels in a number of tissues, most notably the liver in which glycosaminoglycan levels were normalized with an associated dramatic drop in storage granules.…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

Potential of AAV vectors in the treatment of metabolic disease

et al. 2008

View full text Add to dashboard Cite

Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus

Cited by 82 publications

References 34 publications

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

Potential of AAV vectors in the treatment of metabolic disease

Contact Info

Product

Resources

About