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

• 批准号: 7564888
• 负责人: Andras Komaromy
• 金额: $ 48.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564888
• 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 Progression; Disease model; Europe; Evaluation; Eye; Functional disorder; Gene Expression; Generic Drugs; Genomics; Goals; Health; Hereditary Disease; Human; Inherited; Lead; Life; Mediating; Messenger RNA; 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

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. PUBLIC HEALTH RELEVANCE: The cone photoreceptors in the retina are responsible for day- and color vision. These cones are lost in many diseases of the retina which lead to severe vision deficit and even blindness. This research proposal focuses on the development of a new gene therapy to recover diseased cones and their function and to restore day-vision

描述（由申请人提供）：视锥细胞感光器负责中心视敏度、色觉和明视，因此对人类日常生活中的视觉性能至关重要。因此，当设计用于视网膜疾病（例如主要影响视锥细胞的色盲、视锥细胞营养不良和视锥细胞-视杆细胞营养不良）的治疗性治疗时，靶向视锥细胞是极其重要的。然而，在视锥细胞受到继发性影响的疾病中，视锥细胞拯救甚至更重要，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），这是65岁以上人群视力丧失的主要原因。该提案的首要目标是开发2种天然犬色盲模型，作为重组腺相关病毒（rAAV）介导的视锥细胞定向基因治疗的平台。在两种犬模型中，锥环核苷酸门控通道β亚基（CNGB 3）的功能丧失突变导致与人类色盲相同的疾病表型。CNGB 3突变是人类色盲的最常见原因，使2种犬品系成为进行具有翻译潜力的视锥靶向基因置换研究的最佳动物模型。rAAV介导的视网膜基因治疗原发性视网膜色素上皮（RPE）缺陷的长期成功已在包括狗在内的几个物种中得到证实。由于其成功、稳定和明显安全的转基因表达，这些研究现在处于1期临床试验。与RPE缺陷相比，原发性感光细胞疾病的治疗更加困难，并且先前的基因治疗研究已经显示出可变的成功。在该提议中待测试的假设是，在锥特异性启动子的控制下，使用rAAV介导的锥定向递送野生型CNGB 3 cDNA，可以恢复锥功能和结构，并防止退化。为了检验这一假设，我们特别提出1）优化rAAV载体用于视锥中的靶向基因表达，和2）在两种犬模型中CNGB 3 cDNA的视锥特异性表达后最大限度地保留视锥功能。前两个目标的结果将提供有关治疗有效性、安全性和局限性的数据。在最终目标中，犬CNGB 3突变的功能，结构和分子疾病相关性将被表征，并在成功的基因治疗后评估其潜在的逆转，以更充分地了解疾病机制，并为建立最佳治疗时间窗提供疾病指标。犬色盲模型提供了独特的机会，证明锥定向基因治疗的原则，并最终翻译给患者。 公共卫生相关性：视网膜中的锥状光感受器负责白天和颜色视觉。这些视锥细胞在许多视网膜疾病中丢失，导致严重的视力缺陷甚至失明。这项研究计划的重点是开发一种新的基因疗法，以恢复患病的视锥细胞及其功能，并恢复白天视力