Helper-dependent adenoviral (HDAd) vectors are devoid of all viral genes and result in long-term transgene expression in the absence of chronic toxicity. Because of their ability to infect post-mitotic cells, including cells of the central nervous system, HDAd vectors are particularly attractive for brain-directed gene therapy. In this study, we show that intrathecal injection of HDAd results in extensive transduction of ependymal cells and sustained expression of the transgene up to 1 year post-administration. We also demonstrate, for the first time, the ability of HDAd injected by this route of delivery to transduce neuronal cells. The transduced neuroepithelial cells can be potentially used to secrete therapeutic proteins into the cerebrospinal fluid and provide them via cross-correction to nontransduced cells. Targeting of neuronal cells and long-term transgene expression make this approach attractive for the treatment of several neurologic diseases.
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"At the microscopic level, intracerebroventricular injection of AAV1 vector showed exclusive transduction of ependymal cells lining the ventricles and the choroid plexus forming the blood-CSF barrier (Figure 1 and 4). This is similar to the transduction pattern seen after intracerebroventricular injection of other serotypes of AAV1519 or adenoviral vector121314. Although AAV1 vector has been reported to achieve broader neuronal transduction if they were injected into the lateral ventricles of neonatal mouse20, matured ependymal cells would prevent their transfer from the CSF to the brain parenchyma in adult mice because the maturation of ependymal cells occurs during the first postnatal week21. "
[Show abstract][Hide abstract]ABSTRACT: Enzyme replacement via the cerebrospinal fluid (CSF) has been shown to ameliorate neurological symptoms in model animals with neuropathic metabolic disorders. Gene therapy via the CSF offers a means to achieve a long-term sustainable supply of therapeutic proteins within the central nervous system (CNS) by setting up a continuous source of transgenic products. In the present study, a serotype 1 adeno-associated virus (AAV1) vector was injected into a lateral cerebral ventricle in adult mice to transduce the gene encoding human lysosomal enzyme arylsulfatase A (hASA) into the cells of the CNS. Widespread transduction and stable expression of hASA in the choroid plexus and ependymal cells was observed throughout the ventricles for more than 1 year after vector injection. Although humoral immunity to hASA developed after 6 weeks, which diminished the hASA levels detected in CSF from AAV1-injected mice, hASA levels in CSF were maintained for at least 12 weeks when the mice were tolerized to hASA prior of vector injection. Our results suggest that the cells lining the ventricles could potentially serve as a biological reservoir for long-term continuous secretion of lysosomal enzymes into the CSF following intracerebroventricular injection of an AAV1 vector.
" the MPS VII animals to achieve robust , long - term transgene expres - sion in this study . However , immune response is dose de - pendent . The low transgene expression obtained in MPS IIIA animals may allow the escape of the immune response , but it is not sufficient to elicit a significant therapeutic effect in the MPS IIIA model . Similarly , Dindot et al . ( 2011 ) achieved long - term expression after intrathecal administration of human HD adenovirus coding for GFP in a wild - type mouse . The authors administered 2 . 5 · 10 9 pp / mouse into the 40 ll volume that constitutes the mouse CSF . Here we injected a similar amount of pp but concentrated into a single injection in the brain parenchyma"
[Show abstract][Hide abstract]ABSTRACT: Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders due to their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing ß-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in ß-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction. Following intracranial administration of HD-RIGIE, we show long-term expression of ß-glucuronidase that led to correction of neuropathology around the injection site and in distal areas. This phenotypic correction correlated with a decrease in secondary-elevated lysosomal enzyme activity and glycosaminoglycan levels, consistent with global biochemical correction. Moreover, HD-RIGIE-treated mice show significant cognitive improvement. Thus, injections of HD-CAV-2 vectors in the brain allow a global and sustained expression and may have implications for a brain therapy in patients with lysosomal storage disease.
Full-text · Article · Dec 2013 · Human gene therapy
[Show abstract][Hide abstract]ABSTRACT: INTRODUCTION: Lysosomal storage disorders (LSDs) encompass more than 50 distinct diseases, caused by defects in various aspects of lysosomal function. Neurodegeneration and/or dysmyelination are the hallmark of roughly 70% of LSDs. Gene therapy represents a promising approach for the treatment of CNS manifestations in LSDs, as it has the potential to provide a permanent source of the deficient enzyme, either by direct injection of vectors or by transplantation of gene-corrected cells. In this latter approach, the biology of neural stem/progenitor cells and hematopoietic cells might be exploited. AREAS COVERED: Based on an extensive literature search up until March 2011, the author reviews and discusses the progress, the crucial aspects and the major challenges towards the development of novel gene therapy strategies aimed to target the CNS, with particular attention to direct intracerebral gene delivery and transplantation of neural stem/progenitor cells. EXPERT OPINION: The implementation of viral vector delivery systems with specific tropism, regulated transgene expression, low immunogenicity and low genotoxic risk and the improvement in isolation and manipulation of relevant cell types to be transplanted, are fundamental challenges to the field. Also, combinatorial strategies might be required to achieve full correction in LSDs with neurological involvement.
No preview · Article · May 2011 · Expert opinion on biological therapy