Antioxidant treatment as a novel therapeutic option for microvillus inclusion disease (MVID)

微绒毛包涵体病（MVID）是一种非常罕见和严重的遗传性肠病，影响婴儿和幼儿。他们的小肠退化导致患者无法从饮食中吸收营养，使他们终身依赖静脉喂养。不幸的是，大多数患者也死于伴随长期静脉喂养的严重并发症。最近，我们已经确定了MVID中的细胞缺陷，这是小肠变性的原因，重要的是，可以用抗氧化剂N乙酰半胱氨酸（NAC）在MVID小鼠模型中治疗。NAC是一种廉价、安全、EMA/FDA批准的药物，主要用于治疗扑热息痛中毒。虽然NAC用于治疗MVID似乎是合适的，但MVID患者的临床研究并非微不足道。NAC对肠道的长期影响尚不清楚。此外，NAC禁忌用于2岁以下的儿童。在拟议的研究中，我们的目标是优化NAC治疗，并通过使用人类细胞系，类器官和MVID动物模型来确定用于所有年龄段儿童的其他抗氧化药物。此外，我们打算评估最有效且适合MVID患者的药物配方、剂量和给药途径。从这项研究中获得的结果将为首次人体临床试验铺平道路，期待已久的前景是改善营养吸收和减少静脉喂养的需要，最终增加MVID患者的预期寿命和生活质量。

Microvillus inclusion disease (MVID) is a very rare and severe genetic bowel disorder that affects infants and young children. Degeneration of their small intestine causes the patients’ inability to absorb nutrients from the diet and makes them life-long dependent on intravenous feeding. Unfortunately, most patients also die from the severe complications that accompany long-term intravenous feeding. Recently, we have identified a cellular defect in MVID that is accountable for the degeneration of the small intestine and, importantly, could be treated with the antioxidant Nacetylcysteine (NAC) in a mouse model of MVID. NAC is an inexpensive, safe, EMA/FDA-approved drug primarily indicated for the treatment of paracetamol intoxication. Although repurposing of NAC for the treatment of MVID seems fitting, a clinical study in MVID patients is not trivial. The longterm effects of NAC in the intestine are not known. Also, NAC is contraindicated for children under the age of 2. In the proposed study, we aim to optimize NAC treatment and identify other antioxidant drugs for use in children of all ages by using human cell lines, organoids and animal models of MVID. Moreover, we intend to evaluate the drug formulation, dose and route of administration that are most efficient and suitable in MVID patients. The results obtained from this study will pave the way for a first-in-human clinical trial with the long-awaited prospect of improving nutrient absorption and decrease the need for intravenous feeding, ultimately increasing life expectancy and quality of life for MVID patients.