Extra-Adrenal Induction of Cyp21a1 Ameliorates Systemic Steroid Metabolism in a Mouse Model of Congenital Adrenal Hyperplasia

• Project/Area Number: 25461575
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Naiki Yasuhiro 国立研究開発法人国立成育医療研究センター, 内分泌代謝科, 医員 (20470007)
• Co-Investigator(Kenkyū-buntansha): Katsumata Noriyuki 独立行政法人国立成育医療研究センター研究所, 基礎内分泌研究室, 室長 (10260340) ; Fukami Maki 独立行政法人国立成育医療研究センター研究所, 分子内分泌研究部, 部長 (40265872)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 副腎皮質過形成症 / 遺伝子治療 / アデノウィルス随伴ウィルスベクター / 21水酸化酵素欠損症 / 11β水酸化酵素欠損症 / 先天性副腎皮質過形成 / ips細胞 / ES細胞 / アデノウィルス関連ウィルスベクター

Outline of Final Research Achievements

We examined whether transduction of murine Cyp21a1 in extra-adrenal tissues could rescue steroid metabolism in 21-OHD mice to develop a gene therapy for congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency (21-OHD). We injected an adeno-associated viral (AAV) vector containing Cyp21a1 into the thigh muscles of 21-OHD mice. Serum progesterone/DOC ratios were markedly reduced in all four animals at 4 weeks after injection. These results indicate that extra-adrenal induction of Cyp21a1 ameliorates steroid metabolism in 21-OHD mice. We also introduced Cyp21a1 gene using AAV vector containing Cyp21a1 into the adrenal glands of 21-OHD mice. Instead of muscle injection, serum progesterone/DOC ratios did not change at 4 weeks after injection.
We also evaluate the efficacy of induction CYP11B1 gene using AAV vector to the fibroblast CAH due to steroid 11beta-hydroxylase deficiency. The hydroxylation of steroid 11beta hydroxylase was not detected by this method.

Research Products

• [Presentation] 副腎皮質過形成症における副腎皮質外への遺伝子導入による遺伝子治療の試み (2016)
  • Author(s): 内木康博
  • Organizer: 第23回日本ステロイドホルモン学会
  • Place of Presentation: 倉敷芸文館
  • Year and Date: 2016-01-15
• [Presentation] 先天性副腎皮質過形成における副腎外への遺伝子導入における遺伝子治療の試み (2015)
  • Author(s): 内木康博
  • Organizer: 第88回日本内分泌学会
  • Place of Presentation: ホテルニューオータニ
  • Year and Date: 2015-04-23
• [Presentation] Extra-adrenal expression of Cyp21a1 for gene therapy of CAH (2015)
  • Author(s): Yasuhiro Naiki
  • Organizer: 第11回アジア小児科科学研究学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2015-04-15
  • Int'l Joint Research
• [Presentation] 先天性副腎皮質過形成における副腎外への遺伝子導入による遺伝子治療の試み (2014)
  • Author(s): 内木 康博
  • Organizer: 第22回日本ステロイドホルモン学会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-03
• [Presentation] 先天性副腎皮質過形成における副腎外への遺伝子導入による遺伝子治療の試み (2014)
  • Author(s): 内木 康博
  • Organizer: 第48回日本小児内分泌学会
  • Place of Presentation: 浜松
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] EXTRA-ADRENAL EXPRESSION OF Cyp21a FOR GENE THERAPY OF CAH (2014)
  • Author(s): Yasuhiro Naiki
  • Organizer: 16th International congress of Endocrinology/96th The Endocrine Society's Annual Meeting
  • Place of Presentation: Chigago, USA
  • Year and Date: 2014-06-21 – 2014-06-24