Achromatopsia - Disease Mechanisms and Cone-Directed Gene Therapy

全色盲 - 疾病机制和视锥细胞定向基因治疗

基本信息

批准号：
8446968
负责人：
Andras Komaromy
金额：
$ 39.85万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446968
关键词：
Affect Age related macular degeneration Age-Years Anatomy Animal Model Biogenesis Biological Preservation Blindness Canis familiaris Catalytic RNA Color Color Visions Complementary DNA Data Defect Development Disease Disease model Evaluation Eye Functional disorder Gene Expression Gene Proteins Generic Drugs Genomics Goals Health Hereditary Disease Human Inherited Lead Life Mediating Metric Missense Mutation Modality Modeling Molecular Monitor Mus Mutation Patients Pattern Phase I Clinical Trials Phenotype Photoreceptors Process Proteins Publishing Rattus Recombinant adeno-associated virus (rAAV)Reporting Research Proposals Retina Retinal Retinal Cone Retinal Diseases Retinitis Pigmentosa Rodent Model Safety Specificity Staging Structure Structure of retinal pigment epithelium Testing Therapeutic Time Tissues Toxic effect Transgenes Translations Treatment outcome Vision Visual Acuity achromatopsia adeno-associated viral vector age effect base cyclic-nucleotide gated ion channels design disease phenotype early onset gain of function mutation gene replacement gene replacement therapy gene therapy improved loss of function mutation man monolayer mutant neurotrophic factor prevent promoter public health relevance restoration success transgene expression visual performance

项目摘要

DESCRIPTION (provided by applicant): Cone photoreceptors are responsible for central visual acuity, color vision, and photopic vision and are therefore critical for visual performance in daily human life. As such, it is of utmost importance to target cones when designing therapeutic treatment for retinal diseases such as achromatopsia, cone dystrophies, and cone-rod dystrophies that primarily affect cones. However, cone rescue is of even greater importance in diseases where cones are affected secondarily, such as in retinitis pigmentosa (RP) and most forms of age-related macular degeneration (AMD), the leading cause of vision loss in people over 65 years of age. The overarching aim of this proposal is to develop 2 natural canine achromatopsia models as a platform for recombinant adeno-associated virus (rAAV)-mediated cone-directed gene therapy. In both canine models, loss-of-function mutations in the cone cyclic nucleotide-gated channel beta subunit (CNGB3) lead to a disease phenotype identical to human achromatopsia. Mutations in CNGB3 are the most common cause for achromatopsia in man, making the 2 canine strains the optimal animal model in which to carry out cone-targeted gene replacement studies with translational potential. The long-term success of rAAV-mediated retinal gene therapy for primary defects of the retinal pigment epithelium (RPE) has been demonstrated in several species, including dogs. Because of their successful, stable, and apparently safe transgene expression, these studies are now in Phase 1 clinical trials. In contrast to RPE defects, the treatment of primary photoreceptor diseases is more difficult, and previous gene therapy studies have shown variable success. The hypothesis to be tested in this proposal is that cone function and structure can be restored, and degeneration prevented, using rAAV-mediated cone-directed delivery of wildtype CNGB3 cDNA under control of cone-specific promoters. To test this hypothesis, we specifically propose to 1) optimize rAAV vectors for targeted gene expression in cones and 2) maximize preservation of cone function following cone-specific expression of CNGB3 cDNA in the two canine models. Results from the first two aims will provide data regarding the efficiency, safety, and limitations of the treatment. In the final aim, functional, structural, and molecular disease correlates of the canine CNGB3 mutations will be characterized and their potential reversal following successful gene therapy assessed in order to more fully understand disease mechanisms and to provide disease metrics for establishing an optimal therapeutic time window. The canine achromatopsia models offer unique opportunities for proof-of-principle of cone-directed gene therapy and for eventual translation to patients.

描述（由申请人提供）：视锥细胞负责中央视力、色觉和明视，因此对于人类日常生活中的视觉表现至关重要。因此，在设计主要影响视锥细胞的视网膜疾病（例如全色盲、视锥细胞营养不良和视锥细胞营养不良）时，以视锥细胞为目标至关重要。然而，对于视锥细胞受到继发性影响的疾病，例如色素性视网膜炎 (RP) 和大多数形式的年龄相关性黄斑变性 (AMD)，视锥细胞挽救更为重要，AMD 是 65 岁以上人群视力丧失的主要原因。年龄。该提案的总体目标是开发 2 种天然犬全色盲模型，作为重组腺相关病毒 (rAAV) 介导的锥体定向基因治疗的平台。在这两种犬模型中，锥体环核苷酸门控通道β亚基（CNGB3）的功能丧失突变会导致与人类全色盲相同的疾病表型。 CNGB3 突变是人类全色盲的最常见原因，这使得这两种犬类品系成为进行具有转化潜力的锥体靶向基因替换研究的最佳动物模型。 rAAV 介导的视网膜基因治疗对视网膜色素上皮 (RPE) 原发性缺陷的长期成功已在包括狗在内的多个物种中得到证实。由于它们成功、稳定且明显安全的转基因表达，这些研究目前正处于一期临床试验阶段。与 RPE 缺陷相比，原发性光感受器疾病的治疗更加困难，之前的基因治疗研究已显示出不同程度的成功。本提案要测试的假设是，在锥体特异性启动子的控制下，使用 rAAV 介导的锥体定向递送野生型 CNGB3 cDNA，可以恢复锥体功能和结构，并防止退化。为了检验这一假设，我们特别建议 1) 优化 rAAV 载体以实现视锥细胞中的目标基因表达，2) 在两种犬模型中 CNGB3 cDNA 的视锥细胞特异性表达后最大限度地保留视锥细胞功能。前两个目标的结果将提供有关治疗的效率、安全性和局限性的数据。在最终目标中，将描述犬 CNGB3 突变的功能、结构和分子疾病相关性，并评估其在成功基因治疗后的潜在逆转，以便更全面地了解疾病机制并为建立最佳治疗时间窗提供疾病指标。犬全色盲模型为锥定向基因治疗的原理验证和最终转化为患者提供了独特的机会。