AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa
AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa
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DOI：
10.1038/mt.2011.62
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发表时间：
2011-09-01
影响因子：
12.4
通讯作者：
Flannery, John G.
中科院分区：
文献类型：
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作者：
Dalkara, Deniz;Kolstad, Kathleen D.;Flannery, John G.
超过80个已确定的基因突变可诱导光感受器凋亡，导致失明，患病率为1 / 3000。这种影响广泛的光感受器功能的疾病的广泛遗传异质性使得设计光感受器变性的基因特异性治疗变得不切实际，需要开发不依赖突变的治疗来减缓光感受器细胞的死亡。一种有希望的光感受器神经保护策略是从Muller细胞（初级视网膜胶质细胞）分泌神经营养因子。Muller胶质细胞是分泌神经营养因子的极好靶点，因为它们遍布整个组织，包住所有神经元群，数量众多，并在视网膜变性过程中持续存在。我们之前设计了一种腺相关病毒（AAV）变体（ShH10），能够通过玻璃体内注射高效和选择性地传导胶质细胞。shh10介导的神经胶质源性神经营养因子（GDNF）从神经胶质细胞分泌，在治疗视网膜中产生高水平的GDNF，导致持续超过5个月的功能恢复。在视网膜色素变性（RP）大鼠模型中，玻璃体内载体给药后胶质细胞分泌GDNF是一种安全有效的减缓视网膜变性进展的方法，并显示出作为一种基因疗法治疗人类视网膜变性的重大前景。这些发现也首次表明，神经胶质介导的神经营养因子分泌是一种有希望的治疗方法，可能适用于其他神经退行性疾病。
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.