Intrathecal Injection of Helper-Dependent Adenoviral Vectors Results in Long-Term Transgene Expression in Neuroependymal Cells and Neurons

College of Veterinary Medicine and Biomedical Sciences, Veterinary Pathobiology, Texas A&M University, College Station, TX 77843-4467, USA.
Human gene therapy (Impact Factor: 3.76). 12/2010; 22(6):745-51. DOI: 10.1089/hum.2010.147
Source: PubMed


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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Available from: Pasquale Piccolo, Oct 05, 2015
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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. "
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    • " 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"
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