Intracranial Injection of Recombinant Adeno-associated Virus Improves Cognitive Function in a Murine Model of Mucopolysaccharidosis Type VII

Abstract

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by the lack of beta-glucuronidase (GUSB) activity. GUSB deficiency leads to the progressive accumulation of undegraded glycosaminoglycans (GAGs) in cells of most tissues, including the brain, and is associated with mental retardation. Reduction of lysosomal storage in the central nervous system and prevention of cognitive dysfunction may require intracranial delivery of a therapeutic agent during the newborn period that provides a continuous source of GUSB. Therefore, we injected recombinant adeno-associated virus encoding human GUSB into both the anterior cortex and the hippocampus of newborn MPS VII mice. Total GUSB activity in the brain approached normal levels by 18 weeks. Although GUSB activity was concentrated near the injection sites, lysosomal distension was reduced in most areas of the brain. In addition to histopathologic evidence of GAG reduction, the previously undescribed accumulation of GM2 and GM3 gangliosides in the brain was also prevented. Furthermore, GUSB expression and reduced lysosomal distension correlated with improvements in cognitive function as measured in the Morris Water Maze test. These findings indicate that localized overexpression of GUSB has positive effects on the pathology and cognitive function and does not have overt toxicity.

AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL

“…35,36 In the present study, we utilized the CMV-enhanced chicken b-actin promoter with the b-actin/rabbit b-globin hybrid intron, a promoter/intron combination that has been shown to successfully drive the expression of an AAV vector-mediated transfer of a gene in the brain for 41 year. 16 The combination of the long-term expressing vector AAV2 and a strong nonviral promoter led to robust TPP-I expression in the brain of rats for 418 months and for at least 3 months (the longest time period examined to date) in the brains of non-human primates in the present study. Owing to resources needed, there is limited data on long-term transgene expression in nonhuman primates beyond 90 days as described here, although one report shows persistent expression up to 134 days.…”

“…[11][12][13][14][15][16][17] Second, mucopolysaccharidosis VII, a related lysosomal storage disease, has been successfully reversed in a knockout mouse model by recombinant AAV2-mediated intracranial gene transfer. 16,[18][19][20] Third, a significant fraction of newly synthesized TPP-I protein is secreted as pro-TPP-I, a 563 amino-acid inactive form which can crosscorrect nearby nontransduced cells through mannose 6-phosphate receptor-mediated uptake and subsequent activation in lysosomes to the 367 amino-acid mature form. 21,22 This cross-correction between transduced cells and neighboring cells suggests that it will not be necessary to transfer the normal CLN2 cDNA to all the cells in the CNS, thus extending the effective range of gene transfer to broader regions of the brain.…”

Adeno-associated virus vector-mediated transduction in the cat brain

“…In the mouse brain, gene transfer using three recombinant AAV serotypes, AAV2, AAV4, and AAV5, with a variety of promoters and genes has been performed. [3][4][5]7,8,17,[31][32][33][34] All but two studies examined AAV2-mediated transduction alone. 17,35 A direct comparison of intracerebral injection in adult mice of AAV2, AAV4, and AAV5, each containing the Rous sarcoma virus (RSV) long-terminal repeat promoter and the lacZ gene, found that AAV2 and AAV5 could transduce cells in the striatum, but that AAV5 resulted in greater numbers of positive cells at longer time points, whereas, AAV4 resulted in almost exclusive transduction of ependymal cells.…”

Intrathecal enzyme replacement therapy: Successful treatment of brain disease via the cerebrospinal fluid

“…Many invasive strategies have been used or proposed for circumventing the blood-brain barrier, including intraparenchymal injections of therapeutic proteins, intraparenchymal gene therapy, chemical or physical agents to open the blood-brain barrier (such as mannitol), and hematopoietic stem cell transplantation [1][2][3][4][5][6][7][8][9]. Treatment via the cerebrospinal fluid has not been successful in the past due to the inability of the proteins to traverse the ependymal layer and diffuse through brain tissue, even though this route would be clinically easier for application to patients.…”