Longitudinal Neuroimaging of Leber's Congenital Amaurosis After Gene Therapy

描述（由申请人提供）：Leber’s Congenital Amaurosis （LCA）是一种罕见的视网膜疾病，有14种不同的已知基因突变。LCA2是由RPE65突变引起的LCA的一种形式，这种形式在动物和人类中都适用于基因增强治疗。在费城儿童医院（CHOP）， LCA2患者目前正在接受基因治疗以恢复视力的新希望。最近报道了这项临床试验的成功结果。很明显，在人类所有的感觉系统中，视觉为大脑提供了最多的信息，并且有支持证据证实，长期感觉剥夺的个体大脑灰质和白质组织受到影响。一个令人兴奋的问题是，在视力恢复后，这种大脑异常是否可以正常化。利用CHOP的独特机会，本项目在三组受试者中提出了一项纵向综合功能和结构神经影像学研究：第一组是15名LCA2型患者，他们是基因转移治疗的候选人。第二组是10例LCA患者，他们有其他基因突变，不适合手术。第三组是十个视力正常的人。对于LCA2组，将在基线、基因转移后3个月（急性效应）和基因转移后1年（长期效应）获得无创功能和结构脑成像。对于对照组，基线和随访扫描间隔一年。大脑变化将使用CHOP/宾夕法尼亚大学独家提供的最先进的图像采集和处理技术进行评估。成像将在新安装的研究专用3T西门子Verio系统上进行，该系统使用32通道头部线圈。除了灰质和白质的体积，大脑皮层的厚度和皮层折叠也将被评估，尤其是视觉皮层。在基线和随访时，将采用DTI分析和神经束造影来评估受试者体内和受试者之间的视神经通路的变化。视网膜下基因转移手术引起的急性和长期功能改变将使用功能磁共振成像进行研究。提出了具体的功能磁共振成像范式分别评估大脑的一级和二级视觉功能。另一项额外的任务也计划评估可能发生在长期视觉剥夺个体的枕皮质的交叉模态可塑性。在项目结束时，我们希望确定结构/功能脑生物标志物，以预测LCA2患者基因转移治疗的成功。例如，枕皮质白质或灰质体积的基线测量和/或视神经通路的扩散指数可能是患者对基因治疗反应的预测指标。这种结构/功能相关性在未来也可以用于预测基因治疗的成功，旨在恢复其他形式的失明。CHOP和宾夕法尼亚大学拥有独特的成像资源和神经成像专业知识，并在这一独特的患者群体中进行了尖端的临床试验，CHOP是进行这项研究的理想场所。

DESCRIPTION (provided by applicant): Leber's Congenital Amaurosis (LCA) is a rare retinal disease with fourteen different known gene mutations. LCA2 is the form of LCA caused by RPE65 mutations, a form which has been amenable to gene augmentation therapy in both animals and humans. At the Children's Hospital of Philadelphia (CHOP), LCA2 patients are currently being offered with the new hope of gene therapy to restore their vision. Successful results from this clinical trial have been recently reported. It is evident that of all human sensory systems, vision provides the most information to the brain and there is supporting evidence that confirms gray and white matter brain tissue are affected in individuals with prolonged sensory deprivation. An exciting question is whether such brain abnormalities could be normalized after vision is restored. With a unique opportunity at CHOP, this project proposes a longitudinal comprehensive functional and structural neuroimaging study in three groups of subjects: Group 1 is fifteen LCA2 type patients who are candidates for gene transfer therapy. Group 2 is 10 LCA patients with other gene mutations who are not candidates for surgery. Group 3 is ten normally sighted individuals. For the LCA2 group, non-invasive functional and structural brain imaging will be obtained at baseline, three months after gene transfer (acute effect), and one year following gene transfer (long-term effect). For comparison groups, baseline and follow up scans will be obtained one year apart. Brain changes will be assessed using state-of-the-art image acquisition and processing techniques exclusively available at CHOP/University of Pennsylvania. Imaging will be performed on a newly installed research dedicated 3T Siemens Verio system using a 32- channel head coil. In addition to the volume of gray and white matter, cortical thickness and cortical folding of the brain and in particular the visual cortex will be assessed. DTI analyses and tractography will be employed to evaluate the changes in optic pathways within and between subjects at baseline and follow up. Acute and long-term functional changes due to sub-retinal gene transfer surgery will be studied using fMRI. Specific fMRI paradigms are proposed to evaluate the brain's primary and second order visual functions separately. An additional task is also planned to assess the cross modal plasticity of the occipital cortex that may occur in individuals with longstanding visual deprivation. By the end of the project we hope to identify structural/functional brain biomarkers to predict the success of gene transfer treatment for the LCA2 patients. For example, baseline measures of white or gray matter volumes of the occipital cortex and/or diffusion indices of optic pathways may be a predictor of patients' response to gene therapy. Such structural/functional correlations may also be useful in the future for predicting success of gene based therapies aiming to restore vision in other forms of blindness. With the unique imaging resources and neuroimaging expertise available at CHOP and University of Pennsylvania along with the cutting-edge clinical trials conducted on this unique patient population, CHOP is an ideal place to perform this study. PUBLIC HEALTH RELEVANCE: A rare type of pediatric congenital blindness (Leber's Congenital Amaurosis type 2 (LCA2)) is being treated at CHOP using an exciting and advanced method of gene therapy. This proposal will attempt to evaluate functional and structural brain changes before and after gene therapy in a group of previously blind LCA2 patients who have had their vision restored. This would be the first time scientists have evaluated brain changes in humans after vision restoration.