Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates.
Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates.
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DOI：
10.1038/s42003-020-01594-w
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发表时间：
2021-01-27
影响因子：
5.9
通讯作者：
Picaud S
中科院分区：
文献类型：
--
作者：
Gauvain G;Akolkar H;Chaffiol A;Arcizet F;Khoei MA;Desrosiers M;Jaillard C;Caplette R;Marre O;Bertin S;Fovet CM;Demilly J;Forster V;Brazhnikova E;Hantraye P;Pouget P;Douar A;Pruneau D;Chavas J;Sahel JA;Dalkara D;Duebel J;Benosman R;Picaud S
视力恢复是光遗传学的理想医学应用，因为眼睛提供了直接进入视网膜进行刺激的光学通道。光遗传疗法可用于涉及光感受器退化的疾病，如视网膜色素变性或老年性黄斑变性。在这里，我们描述了在非人类灵长类动物中，目前在临床试验中测试的特定光遗传结构的选择。我们使用微生物Opsin ChrimsonR，结果表明AAV2.7m8载体在视网膜神经节细胞(RGCs)中的转染率高于AAV2，并且ChrimsonR与tdTomato融合(chr-TdT)的表达效率高于ChrimsonR。Cm−2.s−1。载体剂量为5 × 1010和5 × 1011 Vg/只眼，在周缘最高可达7000RGCs/mm~2，未见明显免疫反应。我们记录了刺激持续时间大于1 ms时的RGC反应。当使用记录的活动来解码刺激信息时，我们获得了20/249的估计视力，高于法定失明水平(20/400)。这些结果为正在进行的AAV2.7m8-CHR-TDT载体用于视网膜色素变性患者视力恢复的临床试验奠定了基础。Gauvain等人证明，使用AAV2.7m8-CHR-TDT结构的光遗传疗法可以部分恢复非人类灵长类动物的视力，使其达到法律上认为是盲人的水平。这项研究能够确定最适合正在进行的临床试验的结构，试图在视网膜色素变性患者中恢复视力。
Vision restoration is an ideal medical application for optogenetics, because the eye provides direct optical access to the retina for stimulation. Optogenetic therapy could be used for diseases involving photoreceptor degeneration, such as retinitis pigmentosa or age-related macular degeneration. We describe here the selection, in non-human primates, of a specific optogenetic construct currently tested in a clinical trial. We used the microbial opsin ChrimsonR, and showed that the AAV2.7m8 vector had a higher transfection efficiency than AAV2 in retinal ganglion cells (RGCs) and that ChrimsonR fused to tdTomato (ChR-tdT) was expressed more efficiently than ChrimsonR. Light at 600 nm activated RGCs transfected with AAV2.7m8 ChR-tdT, from an irradiance of 1015 photons.cm−2.s−1. Vector doses of 5 × 1010 and 5 × 1011 vg/eye transfected up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. We recorded RGC responses from a stimulus duration of 1 ms upwards. When using the recorded activity to decode stimulus information, we obtained an estimated visual acuity of 20/249, above the level of legal blindness (20/400). These results lay the groundwork for the ongoing clinical trial with the AAV2.7m8 - ChR-tdT vector for vision restoration in patients with retinitis pigmentosa. Gauvain et al demonstrate that optogenetic therapy using the AAV2.7m8- ChR-tdT construct can partially restore vision in non-human primates to levels above those considered legally-blind. This study enables the identification of the most suitable construct for ongoing clinical trials attempting vision restoration in patients with retinitis pigmentosa.
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4.3
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Garita-Hernandez M;Guibbal L;Toualbi L;Routet F;Chaffiol A;Winckler C;Harinquet M;Robert C;Fouquet S;Bellow S;Sahel JA;Goureau O;Duebel J;Dalkara D
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通讯作者：
Lee, B