Longitudinal Neuroimaging of Leber's Congenital Amaurosis After Gene Therapy

基因治疗后莱伯先天性黑蒙的纵向神经影像

• 批准号: 8046670
• 负责人: Manzar Ashtari
• 金额: $ 24.74万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046670
• 关键词: Acute; Affect; Aftercare; Animals; Anisotropy; Area; Auditory; Biological Markers; Blindness; Brain; Brain imaging; Candidate Disease Gene; Childhood; Clinical; Clinical Trials; Conduct Clinical Trials; Control Groups; Data; Deterioration; Diffusion; Diffusion Magnetic Resonance Imaging; Functional Magnetic Resonance Imaging; Future; Gene Mutation; Gene Transfer; Genes; Grant; Head; Human; Image; Image Analysis; Individual; Inferior; Intervention; Knowledge; Leber' s amaurosis; Long-Term Effects; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Methods; Motor; Mutation; Negative Finding; Occipital lobe; Operative Surgical Procedures; Optics; Outcome; Participant; Pathway interactions; Patients; Pediatric Hospitals; Pennsylvania; Philadelphia; Process; RPE65 protein; Reaction Time; Reporting; Research; Resources; Rest; Retinal; Retinal Diseases; Scanning; Schedule; Scientist; Sensory Deprivation; Stimulus; Structure; System; Techniques; Testing; Thick; Time; United States National Institutes of Health; Universities; Vision; Vision Tests; Visual; Visual Cortex; Visual Pathways; Visual system structure; base; blind; brain tissue; comparison group; extrastriate visual cortex; follow-up; gene therapy; gray matter; improved; indexing; luminance; neuroimaging; patient population; research study; response; restoration; sensory system; subretinal injection; success; visual deprivation; white matter

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.

描述（由申请人提供）：Leber的先天性症（LCA）是一种罕见的视网膜疾病，具有14种不同的基因突变。 LCA2是由RPE65突变引起的LCA的形式，这种形式已适合动物和人类的基因增强疗法。在费城儿童医院（CHOP），目前正在向LCA2患者提供基因疗法的新希望，以恢复其视力。最近报道了该临床试验的成功结果。显然，在所有人类感觉系统中，视觉为大脑提供了最多的信息，并且有证据表明证实灰质和白质脑组织在长期剥夺的人中受到影响。一个令人兴奋的问题是，在恢复视力后，这种大脑异常是否可以标准化。该项目在CHOP上有独特的机会，提议在三组受试者中进行纵向综合功能和结构性神经影像学研究：第1组是15名LCA2型患者，它们是基因转移治疗的候选者。第2组是10名LCA患者，患有其他基因突变，不是手术的候选者。第三组是通常有十个人的个人。对于LCA2组，将在基线，基因转移后三个月（急性效应）以及基因转移后一年（长期效应）在基线时获得非侵入性功能和结构脑成像。对于比较组，将获得一年相距一年的基线和后续扫描。将使用最新的图像采集和加工技术评估大脑变化，专门可在宾夕法尼亚大学/宾夕法尼亚大学获得。成像将在新安装的研究专用3T Siemens Verio系统上使用32频道头线圈进行。除了灰质和白质的体积外，还将评估大脑的皮质厚度和皮质折叠，尤其是视觉皮层。将采用DTI分析和拖拉机来评估基线和后续受试者之间和受试者之间的视觉途径的变化。通过fMRI，将研究由于亚视网膜下基因转移手术而引起的急性和长期功能变化。提出了特定的功能磁共振成像范式，以分别评估大脑的主要和二阶视觉功能。还计划进行另一项任务，以评估长期视觉剥夺的个体可能发生的枕皮层的交叉模态可塑性。在项目结束时，我们希望确定结构性/功能性脑生物标志物，以预测LCA2患者基因转移治疗的成功。例如，枕皮层和/或光学途径的扩散指数的白色或灰质体积的基线测量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能对预测旨在恢复其他形式失明的视力的成功疗法的成功。 CHOP是CHOP和宾夕法尼亚大学的独特成像资源和神经影像学专业知识，以及对这个独特的患者人群进行的尖端临床试验，CHOP是进行这项研究的理想场所。 公共卫生相关性：一种罕见类型的小儿先天性失明（Leber的先天性症型2型（LCA2））正在使用一种令人兴奋的高级基因治疗方法进行处理。该建议将尝试评估一组先前盲目的LCA2患者的基因治疗前后的功能和结构性大脑变化，这些患者恢复了视力。这将是科学家第一次评估视力恢复后人类的大脑变化。