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

微绒毛包涵性疾病（MVID）是一种非常罕见和严重的遗传性肠道疾病，影响婴儿和幼儿。小肠退化导致患者无法从饮食中吸收营养，使他们终生依赖静脉喂养。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，我们在MVID小鼠模型中发现了一种导致小肠退化的细胞缺陷，重要的是，它可以用抗氧化剂nacetyl半胱氨酸（NAC）治疗。NAC是一种廉价、安全、经EMA/ fda批准的药物，主要用于治疗扑热息痛中毒。虽然将NAC重新用于MVID的治疗似乎是合适的，但对MVID患者的临床研究并非微不足道。NAC在肠道中的长期影响尚不清楚。此外，NAC禁止用于2岁以下的儿童。在本研究中，我们的目标是通过MVID的人类细胞系、类器官和动物模型来优化NAC的治疗，并确定其他抗氧化药物用于所有年龄段的儿童。此外，我们打算评估最有效和最适合MVID患者的药物配方、剂量和给药途径。这项研究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，最终提高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.