Long-term functional correction of cystathionine β-synthase deficiency in mice by adeno-associated viral gene therapy.
Long-term functional correction of cystathionine β-synthase deficiency in mice by adeno-associated viral gene therapy.
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DOI：
10.1002/jimd.12437
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发表时间：
2021-11
影响因子：
4.2
通讯作者：
Kruger WD
中科院分区：
文献类型：
--
作者：
Lee HO;Salami CO;Sondhi D;Kaminsky SM;Crystal RG;Kruger WD
胱硫醚β-合酶（CBS）缺乏症是一种隐性先天性硫代谢缺陷，其特征是血液中总同型半胱氨酸（tHcy）水平升高。诊断患有 CBS 缺乏症的患者目前通过补充维生素和限制含有同型半胱氨酸前体蛋氨酸的食物相结合的方法进行治疗，但由于依从性差，这种疗法的有效性有限。 CBS 缺陷小鼠模型 (Tg-I278T Cbs−/−) 用于评估治疗 CBS 缺陷的潜在基因治疗方法，该方法利用基于 AAVrh.10 的载体，该载体包含组成型强 CAG 启动子下游的人类 CBS cDNA (AAVrh.10hCBS)。小鼠被注射一剂病毒并进行长达一年的随访。数据表明肝脏 CBS 活性呈剂量依赖性增加，血清 tHcy 呈剂量依赖性下降。一年时肝脏 CBS 酶活性与 Cbs+/- 对照小鼠相似。给予最高剂量（5.6×1011基因组/小鼠）的小鼠在注射一周后平均血清tHcy下降97%，在注射一年后下降81%。接受治疗的小鼠与 Cbs 缺乏相关的脱发、骨质流失和脂肪量表型得到完全或实质性纠正。我们的研究结果表明，基于 AAVrh.10 的基因疗法在治疗小鼠 CBS 缺陷方面非常有效，并支持最终使用人体试验的额外临床前测试。
Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor compliance. A mouse model for CBS deficiency (Tg-I278T Cbs−/−) was used to evaluate a potential gene therapy approach to treat CBS deficiency utilizing an AAVrh.10-based vector containing the human CBS cDNA downstream of the constitutive, strong CAG promoter (AAVrh.10hCBS). Mice were administered a single dose of virus and followed for up to one year. The data demonstrated a dose-dependent increase in liver CBS activity and a dose-dependent decrease in serum tHcy. Liver CBS enzyme activity at one year was similar to Cbs+/− control mice. Mice given the highest dose (5.6×1011 genomes/mouse) had mean serum tHcy decrease of 97% one week after injection and an 81% reduction one year after injection. Treated mice had either full- or substantial correction of alopecia, bone loss, and fat mass phenotypes associated with Cbs deficiency in mice. Our findings show that AAVrh.10-based gene therapy is highly effective in treating CBS deficiency in mice and supports additional pre-clinical testing for eventual use human trials.
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影响因子：
4.2
作者：
Kattenhorn LM;Tipper CH;Stoica L;Geraghty DS;Wright TL;Clark KR;Wadsworth SC
通讯作者：
Wadsworth SC
影响因子：
4.8
作者：
Gupta, Sapna;Melnyk, Stepan B.;Kruger, Warren D.
通讯作者：
Kruger, Warren D.
影响因子：
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通讯作者：
Crystal, Ronald G.
影响因子：
3.5
作者：
Wang, LQ;Chen, XL;Kruger, WD
通讯作者：
Kruger, WD
影响因子：
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作者：
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通讯作者：
Jayandharan, Giridhara R.