Novel Adeno-Associated Viral Therapy for Wet Age-Related Macular Degeneration

新型腺相关病毒疗法治疗湿性年龄相关性黄斑变性

• 批准号: 8392855
• 负责人: Karen Kozarsky
• 金额: $ 30.44万
• 依托单位: REGENX BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392855
• 关键词: Accounting; Adverse event; Age related macular degeneration; Age-Years; American; Antibodies; Blindness; Blood Vessels; Cells; Cicatrix; Clinical; Clinical Trials; Codon Nucleotides; Data; Dependovirus; Development; Disease; Disease Progression; Dose; Drug Costs; Evaluation; Exudative age-related macular degeneration; Eye; Eye Part; Family; Future; Gene Delivery; Gene Expression; Gene Transduction Agent; Gene Transfer; Genes; Genetic; Genome; Goals; Government; Hemorrhage; Human; Immune response; Immunoglobulin Fragments; Injection of therapeutic agent; Investigational Therapies; Measures; Mediator of activation protein; Membrane; Methods; Monoclonal Antibodies; Morbidity - disease rate; Mus; Office Visits; Oxygen; Patients; Persons; Pharmaceutical Preparations; Phase; Photoreceptors; Prevalence; Primates; Recombinant adeno-associated virus (rAAV); Retina; Retinal; Retinal Detachment; Safety; Serotyping; Small Business Innovation Research Grant; Staging; Structure; Structure of retinal pigment epithelium; System; Technology; Testing; Therapeutic; Therapeutic antibodies; Time; TimeLine; Tissues; Transgenic Mice; Treatment Efficacy; United States; Vascular Endothelial Growth Factors; Viral; Vision; adeno-associated viral vector; angiogenesis; base; bevacizumab; cDNA Expression; cellular transduction; disorder control; effective therapy; gene transfer vector; human VEGF protein; human tissue; in vivo; inherited retinal degeneration; inhibitor/antagonist; intravitreal injection; macula; meetings; mouse model; neovascular; neutralizing antibody; nonhuman primate; novel; preclinical safety; promoter; ranibizumab; response; standard of care; subretinal injection; therapeutic gene; therapeutic protein; vector

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a novel gene-based delivery system to treat neovascular age- related macular degeneration (wet AMD), a debilitating ocular disease. AMD is the leading cause of blindness in Americans over 60 years of age, with wet AMD accounting for 90% of all AMD-related blindness. An estimated 2,000,000 people in the United States suffer from wet AMD, and it is expected that the prevalence of wet AMD will grow to 3,000,000 by 2020. Wet AMD is initiated by a thickening and disruption of the membrane underlying the retina. The oxygen supply to the macula is disrupted and the body responds by growing new, abnormal blood vessels. These begin to grow through the breaks of the membrane behind the retina towards the macula, often raising the retina. These abnormal blood vessels tend to be very fragile, and can leak or bleed, causing scarring of the macula. This damage to the macula results in rapid, irreversible central vision loss. The standard of care for wet AMD is repeated intraocular injections of vascular endothelial growth factor (VEGF) inhibitors, including the monoclonal antibody fragment ranibizumab. Optimal control of disease is obtained with monthly injections, which are inconvenient, require frequent office visits, and as is true for any injection into the eye, are associated with morbidity. The proposed therapeutic would be a one-time injection of a gene delivery vehicle, resulting in persistent, stable expression of ranibizumab in the retina. The gene delivery vector belongs to a new family of adeno-associated virus (AAV) serotypes that we identified and which perform substantially better than previously available gene transfer technologies. Recombinant AAV gives stable gene expression in non-dividing tissues without integrating into the genome, and thus avoids potential integration-associated adverse events; furthermore, AAV itself is non-pathogenic. Previously known serotypes of AAV, however, are not very efficient at transducing cells in vivo; the novel AAV serotypes give higher levels of gene expression in the retina, enabling safe and therapeutic gene delivery at lower doses of vector. Gene transfer will be targeted to the RPE and photoreceptors in order to deliver the therapeutic protein directly to the appropriate part of the eye. The immediate goal of this Phase I SBIR application is to identify and develop the optimal clinical candidate. The optimal AAV serotype and promoter for retinal-based gene transfer have been determined. Expression of ranibizumab will be optimized by replacement of the leader sequence and tailoring codon usage for expression in human tissues. Proof of principle studies will be performed by: 1) demonstration of efficacy of the therapeutic in a mouse model of retinal detachment caused by human VEGF expression in the retina, and 2) demonstration and confirmation of previously achieved levels of ranibizumab expression in the non-human primate eye, the species whose retina is closest in structure to the human eye. This will be used for future progression through safety/tox studies and clinical trials. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is one of the leading causes of blindness. The prevalence of neovascular (wet) AMD in the United States is expected to increase to nearly 3 million by 2020. Existing treatments are effective in limiting the progression of the disease but are problematic in both cost of drug and the requirements for frequent administration by intravitreal injection with attendant safety problems. This proposal initiates the clinical development of a new experimental therapy which involves a one-time genetic delivery system using a vector that provides long term expression of the drug which is potentially safer and less burdensome to the patient.

描述（由申请人提供）：该项目的总体目标是开发一种基于基因的新型递送系统，以治疗新生年龄相关的黄斑变性（湿AMD），这是一种令人衰弱的眼部疾病。 AMD是60岁以上美国人失明的主要原因，湿AMD占所有与AMD相关的失明的90％。估计在美国有2,000,000人患有湿AMD，预计到2020年，湿AMD的流行率将增长到3,000,000。湿AMD是通过视网膜下层的膜增厚和破坏而引发的。黄斑的氧气供应受到破坏，人体通过种植新的异常血管做出反应。这些开始通过视网膜后面朝大黄斑的膜的破裂而生长，经常抬起视网膜。这些异常的血管往往非常脆弱，会泄漏或流血，从而导致黄斑疤痕。黄斑的这种损害导致快速，不可逆的中央视力丧失。湿AMD的护理标准是重复的血管内皮生长因子（VEGF）抑制剂（包括单克隆抗体片段ranibizumab）的人工眼内注射。每月注射不方便，需要频繁的办公访问，并以AS为 对于注入眼睛的任何注射都是正确的，与发病率有关。拟议的治疗方法将是对基因输送载体的一次性注射，从而导致视网膜中ranibizumab的持续稳定表达。该基因输送载体属于我们确定的腺相关病毒（AAV）血清型的新系列，其性能比以前可用的基因转移技术更好。重组AAV在不整合基因组的情况下提供了稳定的基因表达，从而避免了潜在的与整合相关的不良事件。此外，AAV本身具有非致病性。然而，以前已知的AAV血清型在体内转导细胞方面并不是很有效。新型的AAV血清型在视网膜中给出了更高水平的基因表达，从而使较低剂量的载体可以安全和治疗性基因递送。基因转移将被靶向RPE和感光体，以将治疗蛋白直接传递到眼睛的适当部分。该阶段I SBIR应用的直接目标是识别和发展最佳临床候选者。已经确定了基于视网膜基因转移的最佳AAV血清型和启动子。 Ranibizumab的表达将通过替换领导者序列和定制密码子用法来优化人类组织中的表达。原则研究证明将通过以下方式进行：1）在视网膜中人类VEGF表达引起的视网膜脱离的小鼠模型中，治疗性的功效证明，以及2）证明和确认先前达到的ranibizumab表达水平的非人类灵长类动物，其在结构上与人眼最接近的物种。这将用于通过安全/托克斯研究和临床试验的未来进展。 公共卫生相关性：与年龄相关的黄斑变性（AMD）是失明的主要原因之一。到2020年，美国新血管（湿）AMD的患病率预计将增加到近300万。现有治疗可有效限制 该疾病的进展，但在药物成本和通过玻璃室内注射和随之而来的安全问题进行频繁给药的要求方面都是有问题的。该提案启动了一种新的实验疗法的临床发展，该疗法涉及使用载体的一次性遗传递送系统，该载体可长期表达该药物，该药物可能更安全，对患者的繁重较小。