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先天性黑色素沉着症(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患者目前被提供了恢复视力的基因治疗的新希望。这项临床试验的成功结果最近已有报道。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，有支持证据证实，长期感觉剥夺的人的灰质和白质脑组织会受到影响。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恢复正常。借助CHOP的一个独特机会，该项目提出了一项针对三组受试者的纵向、全面的功能和结构神经成像研究：第一组是15名LCA2型患者，他们是基因转移治疗的候选对象。第二组是10名LCA患者，他们有其他基因突变，不适合手术。第三组是10个正常视力的个体。对于LCA2组，将在基线、基因转移三个月(急性效应)和基因转移一年(长期效应)后获得非侵入性功能和结构脑成像。对于对照组，基线和后续扫描将每隔一年进行一次。大脑变化将使用最先进的图像采集和处理技术进行评估，该技术仅在CHOP/宾夕法尼亚大学提供。成像将在新安装的研究专用3T西门子Verio系统上进行，使用32通道磁头线圈。除了灰质和白质的体积外，还将评估大脑，特别是视觉皮质的皮质厚度和皮质折叠。DTI分析和纤维束造影术将被用来评估基线和随访时受试者内部和受试者之间的视路变化。视网膜下基因转移手术引起的急性和长期功能变化将使用功能磁共振成像进行研究。具体的fMRI范式被提出用来分别评估大脑的初级和二级视觉功能。还计划进行一项额外的任务，以评估长期视觉剥夺的个体可能发生的枕叶皮质的跨模式可塑性。到项目结束时，我们希望确定结构/功能脑生物标记物，以预测LCA2患者基因转移治疗的成功。例如，枕叶皮质白质或灰质体积和/或视路扩散指数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/功能的相关性在未来也可能有助于预测旨在恢复其他形式失明视力的基于基因的疗法的成功。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，以及在这一独特的患者群体中进行的尖端临床试验，CHOP是进行这项研究的理想地点。 与公共卫生相关：一种罕见的儿童先天性失明(Leber‘s先天性失明2型(LCA2))正在CHOP使用一种令人兴奋的先进基因疗法进行治疗。这项建议将试图评估一组先前失明的LCA2患者在基因治疗前后大脑功能和结构的变化，这些患者已经恢复了视力。这将是科学家第一次评估人类视力恢复后的大脑变化。