Gene-edited T cells combating IgA Nephropathy. A blueprint approach for safe & efficient genome editing of T cells to sustainably combat several immune diseases and cancers related to B-cell pathology

由不受欢迎的免疫反应(10%)引起的慢性病日益流行，对患者(慢性病、器官衰竭、过早死亡、生活质量下降)和社会(欧盟：1000亿欧元/a直接医疗费用)都是沉重的负担，因为目前的治疗方法疗效有限，无法可持续地重塑紊乱的免疫平衡。我们的最终目标是开发一种基于基因组编辑的具有重定向特异性的T细胞的安全有效的细胞疗法，以可持续地对抗IgA肾病(IgAN)--IgA肾病是最常见的肾小球肾炎，也是导致终末期肾脏疾病的最常见原因之一，但药物需求尚未得到满足。我们的特殊细胞治疗方法也适用于其他具有选择性B细胞发病机制的疾病，如IgA骨髓瘤、IgA相关乳糜泻和类风湿性关节炎，但也可作为其他Ig类疾病(如IgG4)的蓝图。我们的新概念通过免疫球蛋白(亚)类靶向&自身免疫性疾病中重定向T细胞的糖基化靶向，提供了一种特定形式的免疫抑制。有条不紊地，我们对三种有前景的基因组编辑技术进行了基准测试，开发了安全性评估和临床前性能评估的新标准。最后，我们将有一种新的“活药物”产品的主要候选者，该产品被设想为一种一次性治疗IgA肾病和其他与IgA相关的药物，将准备进入FIH临床试验(进入TRL6)。此外，GeneTIGA还提供支持技术工具箱，其中包含核心项目之外的开发选项。它们可能会降低风险，并总体上加速下一代基因和细胞产品的开发。因此，除了其科学价值外，该项目不仅对受影响的IgAN患者和相关免疫疾病患者具有很高的影响，而且通过减少渐进性慢性肾脏疾病造成的健康经济负担，以及通过引发欧洲生物技术和制药领域的创新和商业选择，对欧洲社会也具有很高的影响。

There is an increasing prevalence of chronic diseases caused by undesired immune reactions (>10%) with high burden for the both patients (chronicity, organ failure, early death, decreased QoL) and society (EU:>100 bn €/a direct health costs) as current therapies are limited in efficacy and do not reshape sustainably the disturbed immune balance. Our ultimative goal is to develop a safe and efficient cell therapy based on genome-edited T cells with redirected specificity to sustainably combat IgA nephropathy (IgAN) - the most common glomerulonephritis and one of the most common causes of end-stage renal disease with unmet medical need. Our specific cell therapy approach is also suitable for other diseases with selective B-cell pathogenesis, such as IgA myeloma, IgA related celiac disease and rheumatoid arthritis, but as a blueprint also for diseases of other Ig classes (e.g. IgG4). Our novel concept offers a specific form of immunosuppression via Ig-(sub)class targeting & glycosylation targeting with redirected T cells in autoimmune diseases. Methodically, we benchmark three promising genome editing technologies, develop new standards for safety assessment and preclinical performance evaluation. At the end we will have a lead candidate of a new "living drug" product envisioned as a one-time treatment for IgAN and other IgA-associated that will be ready to enter clinical FIH trials (entry into TRL6). In addition, geneTIGA delivers enabling technology toolboxes with exploitation options beyond of the core project. They might de-risk and accelerate the development of next-generation gene and cell products in general. The project has thus, besides its scientific value, a high impact not only on the affected patients with IgAN and related immune diseases, but also for the European society by reducing the health economic burden caused by progressive chronic kidney disease, as well as by triggering innovation and business options in Europe's biotech and pharma field.