کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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4338812 | 1614882 | 2011 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Transgene expression in the striatum following intracerebral injections of DNA nanoparticles encoding for human glial cell line-derived neurotrophic factor Transgene expression in the striatum following intracerebral injections of DNA nanoparticles encoding for human glial cell line-derived neurotrophic factor](/preview/png/4338812.png)
A goal of our studies is to develop a potential therapeutic for Parkinson's disease (PD) by a human glial cell line-derived neurotrophic factor (hGDNF) expression plasmid administered to the rat striatum as a compacted DNA nanoparticle (DNP) and which will generate long-term hGDNF expression at biologically active levels. In the present study, we used a DNA plasmid encoding for hGDNF and a polyubiquitin C (UbC) promoter that was previously shown to have activity in both neurons and glia, but primarily in glia. A two-fold improvement was observed at the highest plasmid dose when using hGDNF DNA incorporating sequences found in RNA splice variant 1 compared with splice variant 2; of note, the splice variant 2 sequence is used in most preclinical studies. This optimized expression cassette design includes flanking scaffold matrix attachment elements (S/MARs) as well as a CpG-depleted prokaryotic domain and, where possible, eukaryotic elements. Stable long-term GDNF activity at levels 300–400% higher than baseline was observed following a single intracerebral injection. In a previous study, DNP plasmids encoding for reporter genes had been successful in generating long-term reporter transgene activity in the striatum (>365 days) and in this study produced sustained GDNF activity at the longest assessed time point (6 months).
▶We tested a non-viral gene transfer technique in brain. ▶Plasmids were optimized to achieve long-term expression in brain tissue. ▶Optimized plasmids were compacted into DNPs and injected into brain. ▶One plasmid/DNP complex achieved long-term transgene activity in brain. ▶DNPs may be a potential therapeutic for Parkinson's disease.
Journal: Neuroscience - Volume 194, 27 October 2011, Pages 220–226