Development of a one-time gene therapy for age-related macular degeneration targeting CD146

开发一种针对 CD146 的针对年龄相关性黄斑变性的一次性基因疗法

• 批准号: 535865618
• 负责人: Professor Dr. Stylianos Michalakis
• 金额: --
• 依托单位: Augenklinik (Innenstadt)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/535865618?language=en
• 关键词: Development; time; gene; therapy; age

Neovascular age-related macular degeneration (wet AMD) is a multifactorial disease leading to loss of central vision. It is the leading cause for blindness in the elderly western population and poses a significant clinical and economic burden. Implementation of anti-VEGF drugs like aflibercept, bevacizumab, ranibizumab and more recently brolucizumab in clinical practice has dramatically improved the prognosis of wet AMD. However, currently there is no cure for wet AMD and available treatments cannot prevent the development of atrophy and scar formation. Thus, it is mandatory to find new treatment options to address the unmet medical need in this devastating sight threatening disease. Here, we propose the development of a one-time gene therapy treatment of AMD based on a novel therapeutic target (CD146; gene name: MCAM). Different from previous approaches that directly inhibit the growth factor VEGFA, our approach targets both the proangiogenic and proinflammatory cell adhesion molecule CD146 to inhibit multiple signaling pathways crucially involved in the pathogenesis of AMD-related vision loss. Own preliminary results suggest that inhibition of CD146 reduces the formation of leaky choroidal blood vessels and the extent of lesion formation in the laser-induced choroidal neovascularization (CNV) mouse model of wet AMD. Previously, we generated variants of recombinant antibody fragments (Fabs) directed against mouse and human CD146 and confirmed high affinity binding to the extracellular domain of human CD146. In this project, we will further characterize the recombinant anti-CD146 Fabs and test dem for efficacy in relevant in vitro models and in the CNV mouse model of wet AMD. The most promising variants will then be produced as AAV-vectorized versions and tested again for in vitro and in vivo efficacy. In an alternative approach, we will generate and test AAV vectors expressing CRISPR-Cas9 and sgRNAs targeting the mouse Mcam gene for inactivation. Our overarching goal is to provide preclinical proof of concept for a novel, one-time gene therapy approach against wet AMD and to select an optimal candidate for future clinical translation.

新生血管性老年性黄斑变性(湿性AMD)是一种导致中心视力丧失的多因素疾病。它是西方老年人口失明的主要原因，并造成重大的临床和经济负担。临床应用的抗血管内皮生长因子药物如阿普利赛特、贝伐单抗、雷尼比珠单抗和新近的溴珠单抗显著改善了湿性AMD的预后。然而，目前还没有治愈湿性AMD的方法，现有的治疗方法也不能阻止萎缩和疤痕的形成。因此，必须找到新的治疗方案来解决这种毁灭性的视力威胁疾病中未得到满足的医疗需求。在这里，我们建议开发一种基于新的治疗靶点(CD146；基因名称：MCAM)的一次性基因治疗AMD。与以往直接抑制生长因子VEGFA的方法不同，我们的方法针对促血管生成和促炎症细胞黏附分子CD146，以抑制在AMD相关性视力丧失发病机制中至关重要的多个信号通路。自身的初步结果表明，在激光诱导的湿性AMD脉络膜新生血管(CNV)小鼠模型中，抑制CD146可以减少渗漏脉络膜血管的形成和病变形成的程度。此前，我们针对小鼠和人CD146产生了重组抗体片段的变体，并证实了与人CD146胞外区的高亲和力结合。在本项目中，我们将进一步鉴定重组抗CD146抗体，并测试DEM在相关体外模型和湿性AMD CNV小鼠模型中的有效性。然后，最有希望的变种将被生产成AAV载体版本，并再次测试体外和体内的疗效。在另一种方法中，我们将产生并测试表达CRISPR-Cas9和针对小鼠MCAM基因的sgRNAs的AAV载体以进行失活。我们的首要目标是为针对湿性AMD的一种新的一次性基因治疗方法提供临床前概念证明，并为未来的临床翻译选择最佳候选者。