The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients.
The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients.
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DOI：
10.1016/j.ophtha.2017.01.029
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发表时间：
2017-06
期刊：
影响因子：
13.7
通讯作者：
Bennett J
中科院分区：
文献类型：
--
作者：
Ashtari M;Nikonova ES;Marshall KA;Young GJ;Aravand P;Pan W;Ying GS;Willett AE;Mahmoudian M;Maguire AM;Bennett J
基因治疗（GT）为那些因RPE 65突变而视力受损的人带来了巨大的希望。虽然GT在招募这些个体的临床试验中取得了巨大成功，但随着时间的推移，这种治疗的稳定性和持久性的证据仍然是未知的。在这里，我们探讨功能性磁共振成像（fMRI）作为一个客观的措施，独立评估视网膜GT的寿命的价值。RPE 65突变的个人，谁经历了GT在他们的视力最差的眼睛在第一阶段的临床试验，在后续的临床试验中，在他们的对侧眼睛接受第二次视网膜下注射。纵向进行功能磁共振成像评估RPE 65患者的大脑反应后，刺激他们最近治疗的眼睛之前和1-3年后GT。7 RPE 65受试者的后续临床试验的一部分分别同意参加纵向神经成像功能磁共振成像研究。所有受试者均使用3特斯拉MRI系统和32通道头部线圈进行fMRI。受试者的皮质激活进行了评估，使用块设计的对比度反转棋盘格刺激使用MRI兼容的视频系统提供的范例。在这项研究中测量的主要参数是定性和定量的功能磁共振成像皮层激活所产生的我们的受试者群体在视觉任务棋盘刺激。功能磁共振成像结果显示，最小或没有皮质反应GT。显着增加皮质激活持续至少三年后GT观察所有科目。重复测量分析显示皮质激活与临床测量之间存在显著相关性，如白色、红色和蓝色的全视野光敏感度阈值（FST）、视野（VF）和瞳孔光反射（PLR）。RPE 65-受试者显示出完整的视觉通路，在治疗后变得有反应并得到加强。fMRI结果独立地揭示了一次性视网膜下注射的有效性和持久性。功能磁共振成像结果与最近报道的相同受试者的长期临床评价结果一致。这项研究的结果表明，功能磁共振成像可能发挥重要作用，为患者的眼科临床评价提供补充信息，并作为未来视网膜干预研究的结果措施的效用。
Gene therapy (GT) has offered immense hope to individuals who are visually impaired due to RPE65 mutations. While GT has shown great success in clinical trials enrolling these individuals, evidence for stability and durability of this treatment over time is still unknown. Here we explore the value of functional magnetic resonance imaging (fMRI) as an objective measure to independently assess the longevity of retinal GT. Individuals with RPE65 mutations, who underwent GT in their worse-seeing eye in a Phase I clinical trial, received a second subretinal injection in their contralateral eye in a follow-on clinical trial. fMRI was longitudinally performed to assess brain responses of RPE65 patients after stimulation of their most recently treated eye before and 1–3 years after GT. Seven RPE65 subjects who were part of the follow-on clinical trial were separately consented to participate in a longitudinal neuroimaging fMRI study. All subjects underwent fMRI utilizing a 3-Tesla MRI system and a 32-channel head coil. Subjects’ cortical activations were assessed using a block design paradigm of contrast reversing checkerboard stimuli delivered using an MRI compatible video system. The primary parameters being measured in this study are the qualitative and quantitative fMRI cortical activations produced by our subject population in response to the visual task checkerboard stimulus. fMRI results showed minimal or no cortical responses before GT. Significant increase in cortical activation lasting at least three years after GT was observed for all subjects. Repeated measures analysis showed significant associations between cortical activations and clinical measures such as full field light sensitivity threshold (FST) for white, red, and blue colors, visual field (VF), and pupillary light reflex (PLR). RPE65-subjects showed intact visual pathways, which became responsive and strengthened after treatment. fMRI results independently revealed the efficacy and durability of a one-time subretinal injection. The fMRI results paralleled those recently reported during the long-term clinical evaluations of the same subjects. Results from this study demonstrate that fMRI may play an important role in providing complementary information to patients’ ophthalmic clinical evaluation and has utility as an outcome measure for future retinal intervention studies.
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影响因子：
15.9
作者：
Ashtari, Manzar;Cyckowski, Laura L.;Bennett, Jean
通讯作者：
Bennett, Jean
影响因子：
3.7
作者：
Ashtari M;Cyckowski L;Yazdi A;Viands A;Marshall K;Bókkon I;Maguire A;Bennett J
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4.2
作者：
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通讯作者：
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影响因子：
4.8
作者：
Goebel, R;Esposito, F;Formisano, E
通讯作者：
Formisano, E