Blood:铁螯合治疗先天性红细胞生成性卟啉症的溶血性贫血和皮肤光敏

2020-07-26 QQY MedSci原创

先天性红细胞生成性卟啉症是由于尿卟啉原III合成酶(UROS)缺乏和非生理性卟啉异构体I代谢物堆积所导致的先天性血红素合成错误。目前,CEP尚无很好治疗方案,减少底物治疗或可改善CEP患者预后。

中心点:
 
铁限制介导ALAS2下调的减少底物治疗有效地减少了CEP中卟啉的积累;
 
铁螯合减轻了卟啉超负荷,逆转了CEP小鼠的溶血性贫血和皮肤光敏性。
 
摘要:
 
先天性红细胞生成性卟啉症(CEP)是由于尿卟啉原III合成酶(UROS)缺乏和非生理性卟啉异构体I代谢物堆积所导致的先天性血红素合成错误。CEP患者的临床特征多样,但通常合并皮肤光敏和慢性溶血性贫血,其严重程度与卟啉超负荷有关。
 
目前,CEP尚无令人满意的治疗方案;现有治疗方案基本都是对症治疗。一种有希望的CEP治疗策略是减少底物治疗(SRT),即通过抑制血红素生物合成途径中的第一个限速酶5-氨基乙酰丙酸合成酶2(ALAS2)来减少卟啉的产生。
 
在CEP病的人红细胞模型中,用RNAi介导下调ALAS2后,Blouin等有效地减少了卟啉蓄积。利用ALAS2的生理性铁依赖转录后调控,研究人员在体外和体内CEP小鼠模型中,评估了用去铁酮来螯合铁是否能够降低ALAS2的表达和随后的卟啉产生。
 
用去铁酮处理UROS缺陷的红系细胞和CEP患者来源的外周血CD34+红系细胞可抑制铁依赖蛋白ALAS2和IRP2的表达,并减少卟啉的产生。
 
此外,在经去铁酮(饮用水:1 mg/ml或3 mg/ml)处理26周的CEP小鼠的红细胞和尿液中,积累的卟啉逐渐减少,皮肤光敏反应也被逆转。在使用最高剂量去铁酮治疗的CEP小鼠中,在铁螯合完全纠正贫血后,溶血和铁超负荷也得到了改善。
 
本研究发现在小鼠和人类模型中都强调了限制铁来调节CEP表型的治疗潜力。
 
原始出处:
 

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    2020-07-28 huirong
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