Astrocyte-specific expression of tyrosine hydroxylase after intracerebral gene transfer induces behavioral recovery in experimental Parkinsonism

Abstract

Parkinson's disease is a neurodegenerative disorder in a rat model of Parkinson's disease produced by lesioncharacterized by the depletion of dopamine in the caudate ing the striatum with 6-hydroxydopamine. Following putamen. Dopamine replacement with levodopa, a precurmicroinjection of the transgene into the denervated striasor of the neurotransmitter, is presently the most common tum as a DNA-liposome complex, expression of the transtreatment for this disease. However, in an effort to obtain gene was detected by RT-PCR and TH protein was better therapeutic results, tissue or cells that synthesize observed specifically in astrocytes by using double-labeling catecholamines have been grafted into experimental aniimmunofluorescence for GFAP and TH coupled with laser mals and human patients. In this paper, we present a novel confocal microscopy. Efficacy was demonstrated by sigtechnique to express tyrosine hydroxylase (TH) in the nificant behavioral recovery, as assessed by a decrease in host's own astrocytes. This procedure uses a transgene in the pharmacologically induced turning behavior generated which the expression of a TH cDNA is under the control of by the unilateral denervation of the rat striatum. These a glial fibrillary acidic protein (GFAP) promoter, which conresults suggest this is a valuable technique to express fers astrocyte-specific expression and also increases its molecules of therapeutic interest in the brain. activity in response to brain injury. The method was tested

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

“…Briefly, the gfa2-LacZ and gfa2-gas1 fragments were excised from the pgfa2LacZ plasmid 16 and pgfa2gas1 vector 10 respectively, using BglII and cloned into the BglII restriction site of the pShuttle vector to produce the AdSLacZ and the AdSGas1 adenoviral vectors. The AdS53 vector was obtained as follows: human p53 cDNA was excised from the pC53-SN3 vector 24 with BamHI and cloned into the BamHI site of the pgfa2MCS plasmid (unpublished results) to obtain the pgfa2p53 plasmid.…”

“…15 Previously, we and other groups have shown that a 2.2 kilobases (kb) fragment of the human glial fibrillary acidic protein (GFAP) promoter (gfa2) is sufficient to regulate the targeted expression of different transgenes in astrocytes, glioma cell lines and primary astrocyte cultures. 11,[16][17][18] Importantly, glial-specificity transcription of the gfa2 promoter was preserved, independently of the gene transfer method employed 11,[19][20][21] and the gfa2 promoter has been used to study the role of glial cells in neurogenesis using transgenic mice. 22 In this study, we examined the effect of different adenoviral systems to target specifically the expression of both gas1 and p53 transgenes to glioma cells.…”

Getting into the brain: liposome-based strategies for effective drug delivery across the blood–brain barrier

“…101 Lastly, novel liposomal formulations have been characterized and efficacy in PD rats reported after intracerebral injection. [125][126][127][128][129][130] As the injection was at the local site of the disease and did not show any evidence of transposing the BBB, they were not considered in this review article.…”

Vectors for the treatment of autoimmune disease

“…In terms of safety, it is also imperative that expression of a therapeutic gene is regulated, so that production can be 188 Salivary gland Sjogren's syndrome Epithelial cells ductal Involucrin promoter 189 Keratinocyte Scleroderma Keratin 14 promoter 190 Basal layer of epidermis Scleroderma Murine albumin gene 127 Liver (hepatocytes) Diabetes and other autoimmune diseases L-type pyruvate kinase promoter 58 Liver (hepatocytes) Diabetes and other autoimmune diseases Rat insulin promoter 191 Pancreatic b-islet cells Diabetes Collagen II promoter 192 Joints (chondrocytes) RA Human glial fibrillary acidic protein promoter 193,194 Brain (astrocytes) MS Neuron-specific enolase promoter 195 Brain (neurones) MS…”