Advancing a novel experimental mRNA-based therapy for Classic Galactosemia

项目总结/摘要 遗传性半乳糖-1-磷酸尿苷酰转移酶（GALT，E.C. 2.7.7.12）人类的活动可以 导致一种称为经典半乳糖血症（OMIM 230400）的潜在致命疾病。尽管有挽救生命的后果 新生儿筛查、早期诊断和半乳糖限制饮食，许多典型半乳糖血症患者在 并发症包括生长、神经心理和语言延迟以及原发性卵巢功能不全 （兴趣点）。目前没有令人满意的治疗方法可用于预防/缓解任何这些并发症。的精确 这些并发症的致病机制尚不清楚，尽管糖蛋白/脂质的异常半乳糖基化 和肌醇磷脂信号传导所造成的长期暴露于有毒中间体的半乳糖代谢受阻 在敏感组织中的途径已经被提出。但是，无论提出的机制和任何相关的 尽管存在争议，但没有人会争论这种疾病的根本原因是受影响的GALT酶活性缺乏。 组织中因此，我们与Moderna Inc.的同事合作。来探索我们是否能增强功能性GALT 在经典半乳糖血症动物模型中使用创新的GALT mRNA疗法的活性。具体来说，我们假设 通过GALT mRNA治疗靶向增强肝脏GALT活性足以恢复全身半乳糖 在典型的半乳糖血症中，其可以促进代谢并改善疾病相关的表型。初步结果表明 在GalT-/-小鼠中静脉注射人GALT mRNA导致活性的、持久的GALT的肝脏表达 酶，该酶快速有效地降低肝脏和其他一些外周组织中的gal-1 P，并显著降低 血浆半乳糖然而，现在判断生物标志物校正是否能导致实际的表型改善还为时过早。因此，我们认为， 我们的目的是在本申请中证明，在肝硬化小鼠模型中， 半乳糖血症足以改善疾病相关表型（目的1），并恢复正常的全身半乳糖 代谢（氧化）（目标2）。如果我们成功了，我们将能够推进这种实验性的mRNA疗法， 临床试验（高回报），这可能会带来一种创新的疗法，以解决患者未满足的医疗需求- 高影响力的结果。此外，关于治疗的最佳时机和预测值的关键信息， 在拟议的工作中揭示的生物标志物将为疾病过程提供重要的见解，并指导 发展其他方式，包括基因治疗。最后但同样重要的是，如果我们能证明半乳糖的恢复 肝脏中的代谢可以导致全身半乳糖氧化的显着改善，这可能导致饮食 松弛（高影响），并且这种治疗策略可以应用于靶向治疗的其他代谢疾病。 最好是（广泛影响）。

PROJECT SUMMARY / ABSTRACT Hereditary deficiency of galactose-1-phosphate uridylyltransferase (GALT, E.C. 2.7.7.12) activity in humans can lead to a potentially lethal disease called Classic Galactosemia (OMIM 230400). Despite the life-saving consequences of newborn screening, early diagnosis, and a galactose-restricted diet, many patients with Classic Galactosemia suffer later in life from complications including growth, neuropsychological, and speech delays as well as primary ovarian insufficiency (POI). There are currently no satisfactory treatments available to prevent/alleviate any of these complications. The precise pathogenic mechanisms of these complications remain unclear, although aberrant galactosylation of glycoproteins/lipids and inositol phospholipid signaling caused by the chronic exposure to toxic intermediates of the blocked galactose metabolic pathway in susceptible tissues have been proposed. But regardless of the proposed mechanisms and any of the associated controversies, no one will debate that the root cause for the disease is the deficiency of GALT enzyme activity in the affected tissues. Therefore, we collaborated with colleagues at Moderna Inc. to explore if we could augment functional GALT activity in an animal model of Classic Galactosemia with an innovative GALT mRNA therapy. Specifically, we hypothesize that targeted augmentation of hepatic GALT activity by GALT mRNA therapy is sufficient to restore whole-body galactose metabolism and ameliorate the disease-relevant phenotypes in Classic Galactosemia. Preliminary results showed that intravenous injection of human GALT mRNA in GalT-/- mice resulted in hepatic expression of active, long-lasting GALT enzyme, which rapidly and effectively reduced gal-1P in liver and some other peripheral tissues and significantly lowered plasma galactose. Yet, it is too early to tell if biomarker correction can lead to actual phenotypic improvements. Therefore, we aim to demonstrate in this application that sole augmentation of hepatic GALT activity in a mouse model of Galactosemia is sufficient to ameliorate the disease-relevant phenotypes (Aim 1) and restore normal whole-body galactose metabolism (oxidation) (Aim 2). If we are successful, we will be able to advance this experimental mRNA therapy to clinical trials (high reward), and this could bring an innovative therapy to address the unmet medical needs of the patients - a high-impact outcome. Moreover, the critical information about the optimal timing of treatment and predictive values of the biomarkers to be revealed in the proposed work will render significant insights to the disease process and guide the development of other modalities, including gene therapy. Last but not least, if we can show that restoration of galactose metabolism in the liver can result in significant improvement of whole-body galactose oxidation, this could lead to diet relaxation (high impact) and such therapeutic strategy could be applied to other metabolic diseases at which targeted therapy is preferred (wide impact).