Adenovirus-mediated gene transfer results in decreased lysosomal storage in brain and total correction in liver of aspartylglucosaminuria (AGU) mouse

Abstract

Aspartylglucosaminuria (AGU) is a lysosomal storage disexpression of AGA was demonstrated in the liver. The ease leading to mental retardation, which is caused by adenovirus vectors were also injected intraventricularly into deficiency of aspartylglucosaminidase (AGA). AGU is the brain of AGU mice resulting in AGA expression in the strongly enriched in the Finnish population in which one ependymal cells lining the ventricles, and further, diffusion major mutation called AGU Fin has been identified. The molof AGA into the neighbouring neurons. Also, AGA enzyme ecular pathogenesis of AGU as well as the biology of the injected intraventricularly was shown to transfer across the AGA enzyme have been extensively studied, thus giving a ependymal cell layer. One month after administration of the profound basis for therapeutic interventions. In this study wild-type Ad-AGA, a total correction of lysosomal storage we have performed adenovirus-mediated gene transfer to in the liver and a partial correction in brain tissue surroundthe recently produced mouse model of AGU, which exhibits ing the ventricles was observed. After administration of the similar pathophysiology as that in humans. Recombinant Ad-AGU virus the lysosomal storage vacuoles in liver or adenovirus vectors encoding for the human AGA and brain remained unchanged. These data demonstrate that AGU Fin polypeptides were first applied in primary neurons the lysosomal storage in AGU can be biologically corrected of AGU mouse to demonstrate wild-type and mutant AGA and furthermore, in the brain a limited number of expression in vitro. In vivo, both of the adenovirus vectors transduced cells can distribute AGA enzyme to the were injected into the tail vein of AGU mice and the surrounding areas.

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

“…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.…”

Expression and Endocytosis of Lysosomal Aspartylglucosaminidase in Mouse Primary Neurons

“…If neurons would maintain their capability to endocytose external enzymes during maturation, as suggested by our in vitro study, the new microglia population derived from BMT might produce sufficient amounts of enzyme to increase the enzyme activity of neurons to the level that exceeds the critical threshold and inhibits the formation of the damaging storage material in neurons. Recent in vivo gene therapy studies with the mouse model of AGU demonstrate that the AGA enzyme actually migrates from cell to cell also in the CNS tissue, which indicates that expression of AGA by a rather small population of neuronal cells may be sufficient to correct the CNS pathology (Peltola, et al, 1998). Although detailed in vivo studies will finally give answers to these important questions, continuous in vitro studies of the proteins in the most vulnerable cell types are required to provide a solid basis for developing therapeutic approaches for neurodegenerative disorders.…”

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

“…In this respect, Niemann-Pick disease type A (NPD-A) is a template for the development of genetic therapies for the neurological manifestations of other LSDs. Various vectors such as adenoviral (Peltola et al, 1998;Ziegler et al, 1999), lentiviral (Bosch et al, 2000;Kim et al, 2004), and adeno-associated viral (AAV) vectors have been used in a number of models of LSD (Barranger and Novelli, 2001;Hsich et al, 2002;Watson and Wolfe, 2003). The efficacy studies most relevant to the present work, however, have been those in which ASM À/À mice received intracerebral injections of an AAV vector encoding human ASM.…”