Development of AAV-AXN-007 gene therapy to treat glaucoma.

AAV-AXN-007基因治疗青光眼的研究进展 摘要： 青光眼是世界上导致不可逆性失明的主要原因，随着 人口老龄化。青光眼的视力丧失是由视网膜神经节细胞进行性退化引起的 (RGC)，但目前还没有得到批准的治疗方法可以直接防止RGC的损失。因为升高的眼内 眼压(IOP)只是已知的可改变的危险因素，目前的护理标准包括降眼压治疗 通过药理学和外科方法。这种慢性的、进行性的、与年龄相关的神经退行性变 混乱是一个紧急的、未得到满足的、全球性的和日益严重的问题，全世界有许多人患有 到2040年，青光眼预计将翻一番，达到1.2亿美元，美国青光眼的年医疗费用 预计到2050年将翻两番，达到170亿美元。应对这一不断上升的医疗和社会经济负担，并 为了改善青光眼患者及其家人的生活，需要新的疾病修正疗法。 青光眼的进行性RGC变性被认为是由于RGC的内在敏感性所致 随着时间的推移，会屈服于这种复杂的神经退行性疾病的慢性病理压力。 在这段时间内对青光眼患者剩余的视网膜节细胞进行干预可以预防其 退化。为了寻找新的治疗靶点，一个无偏的体内AAV2-CRISPR/Cas9筛选&GT；2000 在小鼠视神经挤压模型中，对RGC神经保护基因进行了逐一检测。 在视神经病变动物模型中的这一正向遗传筛查发现了一种神经保护性HIT基因， 当以AAV2-sgRNA为靶点时，可以防止视网膜节细胞在轴突损伤后变性。 此外，据报道，这一途径在青光眼死后视网膜组织中被激活。 患者和视神经损伤后。在这个SBIR应用程序中，我们的目标是验证和测试一个新的 神经保护靶点及AAV2-AXN-007基因治疗对视网膜神经节细胞的保护作用 广泛使用的小鼠微珠阻塞青光眼模型中的轴突和视觉功能。

Development of AAV-AXN-007 gene therapy to treat Glaucoma Abstract: Glaucoma represents the world’s leading cause of irreversible blindness, with its prevalence increasing as the population ages. Vision loss in glaucoma is caused by a progressive degeneration of retinal ganglion cells (RGCs), yet there are no approved therapies that can directly prevent RGC loss. Because elevated intraocular pressure (IOP) is only known modifiable risk factor, current standard of care involves IOP-lowering treatments via pharmacological and surgical approaches. This chronic, progressive, age-related neurodegenerative disorder is an urgent, unmet, global and growing problem, with the number of people worldwide suffering with glaucoma expected to double to ~120 million by 2040, and the annual medical costs of glaucoma in US projected treble to >$17 billion by 2050. To address this escalating medical and socioeconomic burden, and to improve lives of glaucoma patients and their families, novel disease-modifying therapies are needed. Progressive RGC degeneration in glaucoma is thought to result from an intrinsic sensitivity of RGCs that over time succumb to the chronic pathological stresses of this complex neurodegenerative disease. Intervening during this time period in the remaining RGCs of glaucoma patients could prevent their degeneration. To identify new therapeutic targets, an unbiased in vivo AAV2-CRISPR/Cas9 screen of >2,000 genes (tested one-by-one) for RGC neuroprotection in the mouse optic nerve crush model was conducted. This forward genetic screen in an animal model of optic neuropathy discovered a neuroprotective hit gene that, when targeted with AAV2-sgRNA, could prevent RGCs from degeneration following axon damage. Additionally, this pathway has been reported to be activated in post-mortem retinal tissue from glaucoma patients and after optic nerve damage. In this SBIR application, our goal is to validate and test a novel neuroprotective target and AAV2-AXN-007 gene therapeutic approach for its ability to protect RGCs, their axons and visual function in the widely-used mouse microbead occlusion model of glaucoma.