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(申请人提供)：这个项目的总体目标是开发一种新的基于基因的递送系统来治疗新生血管性老年性黄斑变性(湿性AMD)，这是一种令人衰弱的眼部疾病。AMD是60岁以上美国人致盲的主要原因，湿性AMD占所有AMD相关失明的90%。据估计，美国有200万人患有湿性AMD，预计到2020年，湿性AMD的患病率将增长到300万。湿性AMD是由视网膜下膜的增厚和破坏引起的。黄斑的氧气供应被扰乱，身体通过生长新的异常血管来做出反应。它们开始通过视网膜后面的膜破裂向黄斑生长，通常会抬高视网膜。这些异常血管往往非常脆弱，可能会渗漏或出血，导致斑点形成疤痕。这种对黄斑的损害会导致快速的、不可逆转的中心视力丧失。湿性AMD的治疗标准是反复眼内注射血管内皮生长因子(VEGF)抑制剂，包括单抗片段ranibizumab。对疾病的最佳控制是通过每月注射来实现的，这是不方便的，需要经常去办公室，而且 对于任何眼内注射都是正确的，都与发病率有关。拟议的治疗方法将是一次性注射基因载体，导致雷尼比珠单抗在视网膜中持续、稳定的表达。该基因传递载体属于我们鉴定的一种新的腺相关病毒(AAV)血清型家族，其表现明显好于先前可用的基因转移技术。重组AAV在不整合到基因组中的非分裂组织中提供稳定的基因表达，从而避免潜在的整合相关的不良事件；此外，AAV本身是非致病的。然而，以前已知的AAV血清型在体内转导细胞方面并不是非常有效；新的AAV血清型在视网膜中提供了更高水平的基因表达，使得以较低剂量的载体进行安全和治疗性的基因传递成为可能。基因转移将针对RPE和光感受器，以便将治疗性蛋白直接输送到眼睛的适当部位。这一第一阶段SBIR应用的直接目标是确定和开发最佳的临床候选方案。视网膜基因转移的最佳AAV血清型和启动子已经确定。雷尼比珠单抗的表达将通过替换前导序列和调整密码子的使用来优化在人体组织中的表达。原则证明研究将通过以下两个方面进行：1)证明该疗法在人类视网膜血管内皮生长因子表达引起的视网膜脱离小鼠模型中的疗效，以及2)证明和确认以前在非人类灵长类动物眼中实现的雷尼比珠单抗表达水平，该物种的视网膜结构与人眼最接近。这将用于通过安全性/毒性研究和临床试验的未来进展。 公共卫生相关性：老年性黄斑变性(AMD)是导致失明的主要原因之一。预计到2020年，美国新生血管性(湿性)AMD的患病率将增加到近300万。现有的治疗方法有效地限制了 这可能会加速疾病的发展，但在药费和经常通过玻璃体内注射的要求以及伴随的安全问题方面都是有问题的。这项提议启动了一种新的实验性疗法的临床开发，该疗法涉及一种一次性的基因传递系统，使用一种载体提供药物的长期表达，这可能更安全，对患者的负担更小。