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: 8212116
• 负责人: Manzar Ashtari
• 金额: $ 19.29万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212116
• 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; public health relevance; 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先天性黑蒙（LCA）是一种罕见的视网膜疾病，具有14种不同的已知基因突变。LCA 2是由RPE 65突变引起的LCA形式，这种形式在动物和人类中都适用于基因增强疗法。在费城儿童医院（CHOP），LCA 2患者目前正在接受基因治疗的新希望，以恢复他们的视力。最近报道了该临床试验的成功结果。很明显，在所有人类感觉系统中，视觉为大脑提供了最多的信息，并且有支持证据证实，在长期感觉剥夺的个体中，灰质和白色脑组织受到影响。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。在CHOP的独特机会下，该项目提出了三组受试者的纵向综合功能和结构神经影像学研究：第1组是15名LCA 2型患者，他们是基因转移治疗的候选人。第2组是10名患有其他基因突变的LCA患者，他们不适合手术。第三组是十名视力正常的人。对于LCA 2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）获得非侵入性功能和结构脑成像。对于对照组，将间隔一年进行基线和随访扫描。将使用CHOP/University of Pennsylvania独家提供的最先进的图像采集和处理技术评估大脑变化。将在新安装的研究专用3 T Siemens Verio系统上使用32通道头部线圈进行成像。除了灰质和白色物质的体积外，还将评估大脑的皮质厚度和皮质折叠，特别是视觉皮质。将采用DTI分析和纤维束成像评价基线和随访时受试者内和受试者间的视路变化。急性和长期的功能变化，由于视网膜下基因转移手术将使用功能磁共振成像研究。提出了具体的功能磁共振成像模式，分别评估大脑的初级和二级视觉功能。另外一项任务也计划评估枕叶皮层的跨模态可塑性，这可能发生在长期视觉剥夺的个体中。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LCA 2患者基因转移治疗的成功。例如，枕叶皮质的白色或灰质体积和/或视路的扩散指数的基线测量可以是患者对基因治疗的反应的预测因子。这种结构/功能相关性在未来也可能用于预测旨在恢复其他形式的失明的视力的基于基因的治疗的成功。凭借CHOP和宾夕法尼亚大学沿着的独特成像资源和神经成像专业知识，以及对这一独特患者人群进行的尖端临床试验，CHOP是进行本研究的理想场所。 公共卫生关系：一种罕见的儿童先天性失明（Leber先天性黑蒙2型（LCA 2））正在CHOP使用令人兴奋的先进基因治疗方法进行治疗。这项建议将试图评估一组视力恢复的前盲LCA 2患者在基因治疗前后的功能和结构变化。这将是科学家首次评估人类视力恢复后的大脑变化。

项目成果

fMRI of retina-originated phosphenes experienced by patients with Leber congenital amaurosis.

• DOI: 10.1371/journal.pone.0086068
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ashtari M;Cyckowski L;Yazdi A;Viands A;Marshall K;Bókkon I;Maguire A;Bennett J
• 通讯作者: Bennett J

Gene Therapy and Stem Cell Transplantation in Retinal Disease: The New Frontier.

• DOI: 10.1016/j.ophtha.2016.06.041
• 发表时间: 2016-10
• 期刊: Ophthalmology
• 影响因子: 13.7
• 作者: MacLaren RE;Bennett J;Schwartz SD
• 通讯作者: Schwartz SD