Therapeutic effect of prenatal alkalization and PTC124 in Na + /HCO 3 - Cotransporter 1 p.W516∗ knock-in mice

Y. W. Fang, S. S. Yang, T. Chau, M. Nakamura, O. Yamazaki, G. Seki, H. Yamada, H. M. Hsu, C. J. Cheng, S. H. Lin

研究成果: Article査読

6 被引用数 (Scopus)


We created Na + /HCO 3 - cotransporter 1 (NBCe1) p.W516∗ knock-in mice as a model of isolated proximal renal tubular acidosis showing early lethality associated with severe metabolic acidosis to investigate the therapeutic effects of prenatal alkalization or posttranscriptional control 124 (PTC124). NBCe1 W516∗/W516∗ mice were treated with non-alkalization (control, n=12), prenatal alkalization postcoitus (prenatal group, n=7) and postnatal alkalization from postnatal day 6 (postnatal group, n=12). Mutation-specific therapy, PTC124 (60 mg kg -1) or gentamicin (30 mg kg -1), was administered intraperitoneally from postnatal day 6. Blood and urine biochemistry, acid-base analysis, survival rate and renal histology were examined. NBCe1 protein, mRNA abundance and activity ex vivo were assessed after PTC124 and gentamicin treatment. Prenatal group mice had similar initial body weight to wild-type mice and achieved significant weight gain thereafter compared with controls. They had higher serum bicarbonate level (15.5±1.4 vs 5.5±0.1 mmol l -1, P<0.05) on postnatal day 14 and better renal function, histology and survival rates (60.8±23.5 vs 41.1±15.8 days, P<0.05) than the postnatal group. Compared with the control and gentamicin therapies, PTC124 therapy significantly increased NBCe1 protein abundance despite unchanged mRNA transcription. Only PTC124 therapy significantly increased survival rate and partially rescued NBCe1 activity ex vivo. In NBCe1 W516∗/W516∗ mice, prenatal alkali therapy achieved higher survival rates and ameliorated organ dysfunction. PTC124 therapy for this nonsense mutation was partially effective in increasing NBCe1 expression and activity.

ジャーナルGene Therapy
出版ステータスPublished - 2015 5月 9

ASJC Scopus subject areas

  • 分子医療
  • 分子生物学
  • 遺伝学


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