Preclinical Efficacy and Safety of 1-Deoxygalactonojirimycin in Mice for Fabry Disease
Preclinical Efficacy and Safety of 1-Deoxygalactonojirimycin in Mice for Fabry Disease
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DOI：
10.1124/jpet.108.149054
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Fan, Jian-Qiang
中科院分区：
文献类型：
--
作者：
Ishii, Satoshi;Chang, Hui-Hwa;Fan, Jian-Qiang
法布里病是由α -半乳糖苷酶A （α -gal A）活性缺乏引起的先天性鞘糖脂代谢错误。研究表明，在酶活性残差的Fabry患者中发现的大部分突变中，蛋白质错误折叠是导致酶缺乏的主要原因，而1-脱氧半乳糖吉里霉素（DGJ）可以有效地提高培养患者细胞中的残差酶活性。在此，我们在表达人类突变α - gal A活性的转基因小鼠中证明了DGJ的临床前有效性和安全性。心脏、肾脏、脾脏和肝脏α -半乳糖A活性呈剂量和时间依赖性增加。DGJ处理2周后，转基因小鼠心肌细胞和远曲小管中α - gal A突变体表达增加。以约3mg /kg体重/天的剂量治疗4周后，小鼠肾脏中的Globotriaosylceramide储存显著减少。DGJ在所有主要问题中的半衰期均小于1天，在DGJ处理期间合成的酶的半衰期约为4天。DGJ剂量为30 mg/kg体重/天，连续9周未见血液化学异常和病理组织损伤。此外，在连续给予有效剂量DGJ 2年期间，小鼠的外观、生长、生育和寿命均未发生变化。这些临床前结果表明，DGJ在恢复组织中突变酶活性和逆转肾脏中底物储存方面是有效的，并且在小鼠中具有良好的耐受性。
Fabry disease is an inborn error of glycosphingolipid metabolism caused by deficiency of alpha-galactosidase A (alpha-Gal A) activity. It has been shown that protein misfolding is primarily responsible for the enzyme deficiency in a large proportion of mutations identified in Fabry patients with residual enzyme activity, and 1-deoxygalactonojirimycin (DGJ) can effectively increase the residual enzyme activity in cultured patient's cells. Herein, we demonstrate the preclinical efficacy and safety of DGJ in transgenic mice that express human mutant alpha-Gal A activity. alpha-Gal A activity in heart, kidney, spleen, and liver was increased dose- and time-dependently. The mutant alpha-Gal A was increased in cardiomyocytes and distal convoluted tubules of the transgenic mice in a null background after 2 weeks of DGJ treatment. Globotriaosylceramide storage was remarkably reduced in kidney of mice after a 4-week treatment at a dosage of approximately 3 mg/kg body weight/day. The half-life of DGJ was less than 1 day in all major issues and that of the enzyme synthesized during the DGJ treatment period was approximately 4 days. No abnormality of blood chemistry and pathological tissue damage was found in mice treated with DGJ at similar to 30 mg/kg body weight/day for 9 weeks. Furthermore, no change was observed in appearance, growth, fertility, and life span in mice during a 2-year period of continuous administration of DGJ at the effective dosage. These preclinical results indicate that DGJ is effective in restoring mutant enzyme activity in tissues and reversing substrate storage in kidney and is well tolerated in mice.