AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa

被引:78
作者
Dalkara, Deniz [1 ,2 ,3 ,4 ]
Kolstad, Kathleen D. [1 ,2 ]
Guerin, Karen I. [1 ,2 ]
Hoffmann, Natalie V. [1 ,2 ]
Visel, Meike [1 ,2 ]
Klimczak, Ryan R. [1 ,2 ]
Schaffer, David V. [1 ,2 ,3 ,4 ]
Flannery, John G. [1 ,2 ]
机构
[1] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA
[3] Univ Calif Berkeley, Dept Chem Engn, Berkeley, CA 94720 USA
[4] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA
关键词
HIGH-EFFICIENCY TRANSDUCTION; GENE-TRANSFER; PHOTORECEPTOR DEGENERATION; ANIMAL-MODELS; THERAPY; EXPRESSION; VECTORS; PROTECTION; MUTATIONS; DELIVERY;
D O I
10.1038/mt.2011.62
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Mutations in over 80 identified genes can induce apoptosis in photoreceptors, resulting in blindness with a prevalence of 1 in 3,000 individuals. This broad genetic heterogeneity of disease impacting a wide range of photoreceptor functions renders the design of gene-specific therapies for photoreceptor degeneration impractical and necessitates the development of mutation-independent treatments to slow photoreceptor cell death. One promising strategy for photoreceptor neuroprotection is neurotrophin secretion from Muller cells, the primary retinal glia. Muller glia are excellent targets for secreting neurotrophins as they span the entire tissue, ensheath all neuronal populations, are numerous, and persist through retinal degeneration. We previously engineered an adeno-associated virus (AAV) variant (ShH10) capable of efficient and selective glial cell transduction through intravitreal injection. ShH10-mediated glial-derived neurotrophic factor (GDNF) secretion from glia, generates high GDNF levels in treated retinas, leading to sustained functional rescue for over 5 months. This GDNF secretion from glia following intravitreal vector administration is a safe and effective means to slow the progression of retinal degeneration in a rat model of retinitis pigmentosa (RP) and shows significant promise as a gene therapy to treat human retinal degenerations. These findings also demonstrate for the first time that glia-mediated secretion of neurotrophins is a promising treatment that may be applicable to other neurodegenerative conditions.
引用
收藏
页码:1602 / 1608
页数:7
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