Demonstration of POC of a PAX6 saRNA in a model of PAX6 driven Aniridia.

无虹膜是一种罕见的疾病，患者的眼睛因PAX6基因突变而发育不正常。虽然罕见，但这种疾病对患者的生活质量产生了巨大的不利影响。重要的是，尽管这些患者生来就有眼疾，但疾病最严重的方面发生在生命的后期。最大的问题发生在十几岁和二十岁出头，这时眼睛透明的前部角膜开始衰竭，导致大面积疼痛、炎症和透明度丧失。目前，唯一的选择是手术移植健康的角膜，这种复杂的干预只能提供暂时的缓解。在这个项目中，我们将以我们正在进行的工作为基础，开发一种基于基因激活技术的新疗法，我们预计这种疗法将极大地改善患者的生活，减少他们对复杂临床护理的需求。该项目由MiNA therapeutics公司领导，他们是使用一种被称为“RNA激活”的新型药物的世界专家。在这里，我们将利用我们所有的知识，利用RNA激活来挽救PAX6基因的表达。在过去的4年里，我们一直在与利物浦大学的临床科学家和分子生物学家一起研究这个项目，现在我们已经找到了一种候选分子，我们相信它能在细胞中有效地起作用。在这个项目中，我们将在更多相关的模型系统中确认这一发现，作为开始临床前研究和人体临床试验之前的最后一步。具体来说，这个项目将包括对我们的主要候选药物进行一系列有针对性的改变，使其更有效、更稳定、更有效，并确保我们能够将药物输送到眼睛中的适当细胞中。然后，我们将使用一种广泛使用的无虹膜小鼠模型，这种模型已经被彻底地描述过，与人类疾病非常相似。使用这个模型，我们将测试我们的新药，确定最佳剂量和给药方法。

Aniridia is a rare disease where patients' eyes develop improperly due to a genetic mutation in a gene called PAX6\. Although rare, the disease has a dramatic detrimental impact of patients' quality of life. Importantly, although the patients are born with eye problems, the worst aspects of disease occur later in life. The biggest problem occurs in the teens and early twenties when the transparent front part of the eye, the cornea, begins to fail leading to extensive pain, inflammation and loss of transparency. At present, the only options are surgery to transplant healthy cornea and this complicated intervention only provides temporary relief. In this project we will build upon our ongoing work to develop a new treatment based on gene activation technology that we anticipate will dramatically improve patients' lives and reduce their requirement for complicated clinical care.This project is led by MiNA therapeutics who are world-experts at using a new class of drug known as "RNA activation". Here we will use all our knowledge in using RNA activation to rescue expression of the PAX6 gene. We have been working on this project with clinician scientists and molecular biologists at the University of Liverpool for the past 4 years and are now in position with a candidate molecule that we are confident works effectively in cells. In this project, we will confirm this finding in more relevant model systems as the final step before initiating preclinical studies and human clinical trials.Specifically, this project will involve making a series of targeted changes to our lead candidate to make it more effective, more stable and more potent, and to ensure we can deliver the drug to the appropriate cells in the eye. We will then use a mouse model of aniridia that is widely used and has been thoroughly characterised and is very similar to the human disease. Using this model, we will test our new drugs, determining the optimal dose and delivery approaches.