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Interventional approaches for restoring vision

恢复视力的介入方法

基本信息

批准号：
7968421
负责人：
ANAND SWAROOP
金额：
$ 117.9万
依托单位：
NATIONAL EYE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7968421
关键词：
Address Adopted Adult Angiogenesis Inhibitors Animal Model Antibodies Avastin Biological Models Blindness Cell Line Cell Transplants Cells Collaborations Commit DNA Sequence Degenerative Disorder Derivation procedure Disease Drug usage Electroporation Engineering Etiology Europe Exudative age-related macular degeneration Future Gene Delivery Genes Goals In Vitro Injury Interneurons Lucentis Methods Modality Molecular Mus Neuroglia Neurons Pathway interactions Photoreceptors Protocols documentation Recombinants Regulatory Element Research Retina Retinal Retinal Degeneration Retinal Diseases Retinal Photoreceptors Source Stem cells Testing Therapeutic Intervention Transfection Transgenic Mice Transplantation Vision Wild Type Mouse adeno-associated viral vector base bevacizumab gene discovery gene therapy human embryonic stem cell human embryonic stem cell line in vivo interest molecular marker novel novel strategies palliative ranibizumab research study retinal rods subretinal injection tool

项目摘要

Background Research into retinal blinding diseases has attracted considerable efforts. Anti-VEGFA antibodies (ranibizumab or Lucentis and bevacizumab or Avastin ) have recently been introduced in the USA and Europe. Although these anti-angiogenic drugs are used successfully for the treatment of wet AMD, they do not address the disease causation. Similarly, other therapeutic interventions to date are palliative for the majority of retinal degenerative diseases. This highlights the need to better understand the etiology of retinal diseases and to inform new approaches for treatment. Results 1. Gene therapy for early congenital blindness (LCA) In collaboration with Peter Colosi's lab (NNRL), we have initiated gene therapy approaches using rd16 mice as a model system. Several methods are employed to accomplish gene delivery into the retina. One approach involves replacement of the defective gene (Cep290). These methods are being first tested by in vivo electroporation and will be followed by subretinal injection of AAV vectors carrying the DNA sequence of interest. 2. Derivation of photoreceptors from human embryonic stem cell (HESC) and Mller glia cell lines Our goal is to develop optimal conditions for photoreceptor differentiation and identify molecular markers for cells that can be used for transplantation. We are using human embryonic stem cells to generate committed photoreceptors and retinal interneurons in vitro. NIH-approved HESC lines were differentiated to retinal cells and transplanted into the subretinal space of young wild type mice to investigate their potential to integrate into the host retina. The adopted protocol reproducibly generated neurons expressing photoreceptor-specific markers after grafting. In future experiments differentiation of HESCs will be accomplished by transfection of recombinant BACmids engineered to express EGFP and tdTomato under control of endogenous photoreceptor gene regulatory elements. Furthermore, we are testing the hypothesis that by introducing NRL in vivo following retinal injury we will enable Mller glia cells to differentiate into rod photoreceptors. Preliminary results obtained by in vivo electroporation of NRL in adult mice were encouraging. More transgenic mice were generated as tools to further test this hypothesis.

背景