Correction of renal tubular acidosis in carbonic anhydrase II-deficient mice with gene therapy.
Correction of renal tubular acidosis in carbonic anhydrase II-deficient mice with gene therapy.
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通过基因治疗纠正碳酸酐酶 II 缺陷小鼠的肾小管酸中毒。
DOI：
10.1172/jci1694
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Lien,YH
中科院分区：
文献类型：
--
作者：
Lai,LW;Chan,DM;Erickson,RP;Hsu,SJ;Lien,YH
人类碳酸酐酶II（CAII）缺乏与肾小管酸中毒、骨硬化和脑钙化综合征有关。由于点突变导致的CAII缺乏的小鼠品系也表现出肾小管酸中毒。我们在这里报告，逆行注射的阳离子脂质体复合的CAII嵌合基因，使用巨细胞病毒（CMV）的启动子/增强子作为表达盒，以驱动人类CAII cDNA，到肾盂的CAII缺陷小鼠的结果在肾脏中表达的CAII。CAII基因及其相应mRNA的水平在治疗后第3天达到最高，此后逐渐降低，但在1个月时仍可检测到。在基因治疗后，CAII缺陷小鼠在口服氯化铵后恢复了酸化尿液的能力。酸化尿液的能力在基因治疗后3周维持，并最终在6周时丧失。免疫组织化学研究表明，CAII的表达在外髓质和皮质髓质交界处的管状细胞。根据血尿素氮水平和肾组织学评估，基因治疗与肾毒性无关。据我们所知，这是第一个成功的基因治疗遗传性肾病。我们的研究结果表明，基因治疗作为一种新的治疗遗传性肾小管缺陷的潜力。
Carbonic anhydrase II (CAII) deficiency in humans is associated with a syndrome of renal tubular acidosis, osteopetrosis, and cerebral calcification. A strain of mice of CAII deficiency due to a point mutation also manifests renal tubular acidosis. We report here that retrograde injection of cationic liposome complexed with a CAII chimeric gene, using a cytomegalovirus (CMV) promoter/enhancer as an expression cassette to drive human CAII cDNA, into the renal pelvis of CAII-deficient mice results in expression of CAII in the kidney. The levels of both the CAII gene and its corresponding mRNA were highest by day 3 after treatment, diminishing thereafter, but remaining detectable by 1 mo. After gene therapy, CAII-deficient mice restored the ability to acidify urine after oral administration of ammonium chloride. The ability to acidify urine was maintained at 3 wk after gene therapy, and was eventually lost by 6 wk. Immunohistochemistry studies using anti-CAII antibodies showed that CAII was expressed in tubular cells of the outer medulla and corticomedullary junction. The gene therapy was not associated with nephrotoxicity as assessed by blood urea nitrogen levels and renal histology. To our knowledge, this is the first successful gene therapy of a genetic renal disease. Our results demonstrate the potential of gene therapy as a novel treatment for hereditary renal tubular defects.
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CA-II 缺陷小鼠肾碳酸酐酶 (CA) 的定位和活性。
DOI：
10.1016/0005-2736(91)90187-d
发表时间：
1991
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
W. Brechue;E. Kinne;R. Kinne;Thomas H. Maren
通讯作者：
Thomas H. Maren
哺乳动物碳酸酐酶的遗传学。
影响因子：
--
作者：
Tashian,RE
通讯作者：
Tashian,RE
肾脏疾病的基因治疗。
DOI：
--
发表时间：
1997
期刊：
Kidney international. Supplement.
影响因子：
--
作者：
Lien,YH;Lai,LW
通讯作者：
Lai,LW
影响因子：
4.2
作者：
Song, YK;Liu, F;Liu, DX
通讯作者：
Liu, DX
DOI：
10.1073/pnas.90.23.11307
发表时间：
1993-12-01
影响因子：
11.1
作者：
NABEL, GJ;NABEL, EG;CHANG, AE
通讯作者：
CHANG, AE