Schümann Jens, Grevot Armelle, Ledieu David, Wolf Armin, Schubart Anna, Piaia Alessandro, Sutter Esther, Côté Serge, Beerli Christian, Pognan François, Billich Andreas, Moulin Pierre, Walker Ursula Junker
Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland
Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland.
Toxicol Pathol. 2015 Jul;43(5):694-703. doi: 10.1177/0192623314565650. Epub 2015 Jan 27.
Sphingosine-1-phosphate (S1P) lyase is considered as a drug target in autoimmune diseases based on the protective effect of reducing activity of the enzyme in animal models of inflammation. Since S1P lyase deficiency in mice causes a severe, lethal phenotype, it was of interest to investigate any pathological alterations associated with only partially reduced activity of S1P lyase as may be encountered upon pharmacological inhibition. Both genetic reduction of S1P lyase activity in mice and inhibition of S1P lyase with a low-molecular-weight compound in rats consistently resulted in podocyte-based kidney toxicity, which is the most severe finding. In addition, skin irritation and platelet activation were observed in both instances. The similarity of the findings in both the genetic model and the pharmacological study supports the value of analyzing inducible partially target-deficient mice for safety assessment. If the findings described in rodents translate to humans, target-related toxicity, particularly podocyte dysfunction, may limit chronic systemic treatment of autoimmune diseases with S1P lyase inhibitors. Furthermore, partial deficiency or inhibition of S1P lyase appears to provide an in vivo rodent model to enable studies on the mechanism of podocyte dysfunction.
基于在炎症动物模型中降低鞘氨醇-1-磷酸（S1P）裂解酶活性具有保护作用，该酶被视为自身免疫性疾病的药物靶点。由于小鼠中S1P裂解酶缺乏会导致严重的致死表型，因此研究与药理学抑制时可能出现的S1P裂解酶活性仅部分降低相关的任何病理改变很有意义。小鼠中S1P裂解酶活性的基因降低以及用低分子量化合物在大鼠中抑制S1P裂解酶均一致导致以足细胞为基础的肾毒性，这是最严重的发现。此外，在这两种情况下均观察到皮肤刺激和血小板活化。基因模型和药理学研究结果的相似性支持了分析诱导性部分靶点缺陷小鼠用于安全性评估的价值。如果在啮齿动物中描述的结果适用于人类，与靶点相关的毒性，尤其是足细胞功能障碍，可能会限制用S1P裂解酶抑制剂对自身免疫性疾病进行慢性全身治疗。此外，S1P裂解酶的部分缺陷或抑制似乎提供了一种体内啮齿动物模型，以便能够研究足细胞功能障碍的机制。
