Multiple development of treatment for pulmonary arterial hypertension by constitutive active natriuretic peptide receptor

• Project/Area Number: 15K09690
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Osaka University
• Principal Investigator: Kogaki Shigetoyo 大阪大学, 医学系研究科, 招へい教員 (00311754)
• Co-Investigator(Kenkyū-buntansha): 高橋 邦彦 大阪大学, 医学系研究科, 招へい教員 (10610230) ; 那波 伸敏 大阪大学, 医学部附属病院, 医員 (30617543) ; 馬殿 洋樹 大阪大学, 医学部附属病院, 医員 (60644614)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 小児循環器学 / 肺高血圧症 / 遺伝子治療

Outline of Final Research Achievements

We analyzed the effect of the induction of constitutive active NPR2, which could produce massive cGMP compared to other drugs. NPR2 was induced by using Sendai-virus vectors into Sugen-Hypoxia model rat which was shown as very similar to human pulmonary hypertension. First we confirmed the safety of this treatment by immunostaining of Sendai virus, which showed no infection except for lungs. The NPR2 induction leaded significant improvement of pulmonary arterial pressure by catheter examination. In histologically, NPR2 induction demonstrated the improvement of medial wall thickness of pulmonary resistant arteries as well as the supression of small pulmonary vessel occlusion.
Next, we identified candidate small compounds, which allowed to access and stimulate guanylyl cyclase activity of NPR2 by using in silico modeling of the molecular structure of NPR2. However no small compound showed significant superior stimulative activity compared to existing drugs.

Research Products

• [Journal Article] Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension. (2016)
  • Author(s): Nawa N, Ishida H, Katsuragi S, Baden H, Takahashi K, Higeno R, Torigoe F, Mihara S, Narita J, Miura K, Nakamura K, Kogaki S, Ozono K.
  • Journal Title: Mol Ther Methods Clin Dev Volume: 3 Pages: 16044-16044
  • DOI: 10.1038/mtm.2016.44
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic predictive value of gene mutations in Japanese patients with hypertrophic cardiomyopathy. (2016)
  • Author(s): Chida A, Inai K, Sato H, Shimada E, Nishizawa T, Shimada M, Furutani M, Furutani Y, Kawamura Y, Sugimoto M, Ishihara J, Fujiwara M, Soga T, Kawana M, Fuji S, Tateno S, Kuraishi K, Kogaki S, Nishimura M, Ayusawa M, Ichida F, Yamazawa H, Matsuoka R, Nonoyama S, Nakanishi T.
  • Journal Title: Heart Vessels Volume: Nov 24 Issue: 6 Pages: 700-707
  • DOI: 10.1007/s00380-016-0920-0
  • Peer Reviewed / Open Access
• [Presentation] B型ナトリウム利尿ペプチド受容体（NPR-B）機能獲得変異体による心不全予防効果の検討 (2016)
  • Author(s): 馬殿洋樹，桂木慎一，那波伸敏，石田秀和，成田淳，高橋邦彦，小垣滋豊，大薗恵一
  • Organizer: 第52回日本小児循環器学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-07-06
• [Presentation] Intravascular injection of Sendai virus vector carrying continuously cGMP producing mutant of type B Natriuretic Peptide Receptor can ameliorate pulmonary arterial hypertension. (2015)
  • Author(s): Nawa N, Ishida H, Katsuragi S, Baden H, Takahashi K, Kogaki S, Higeno R, Torigoe F, Mihara S, Narita J, Miura K, Ozono K
  • Organizer: American Heart Association (AHA) Scientific Sessions 2015
  • Place of Presentation: Orlando, Florida, United States
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] CNP受容体恒常活性型変異体を用いた肺高血圧症の新たな治療法 (2015)
  • Author(s): 那波 伸敏、石田 秀和、馬殿 洋樹、桂木 慎一、高橋 邦彦、小垣 滋豊、廣瀬 将樹、鳥越 史子、髭野 亮太、三原 聖子、成田 淳、三浦 弘司、大薗 恵一
  • Organizer: 第4回日本肺循環学会・第3回日本肺高血圧学会 合同学術集会
  • Place of Presentation: ステーションコンファレンス東京
  • Year and Date: 2015-10-03
• [Presentation] センダイウイルスベクターを用いた 肺動脈性肺高血圧症(PAH)に対する新たな遺伝子治療の可能性 (2015)
  • Author(s): 那波 伸敏、石田 秀和、馬殿 洋樹、高橋 邦彦、小垣 滋豊、廣瀬 将樹、桂木 慎一、髭野 亮太、三原 聖子、成田 淳、三浦 弘司、大薗 恵一
  • Organizer: 第51回日本小児循環器学会総会・学術集会
  • Place of Presentation: ホテル日航東京
  • Year and Date: 2015-07-16
• [Presentation] Therapeutic application of constitutively active type B natriuretic peptide receptor for pulmonary arterial hypertension (2015)
  • Author(s): Nawa N, Ishida H, Baden H, Takahashi K, Higeno R, Mihara S, Ishii R, Ichimori H, Yabushita-Okada Y, Miura K, Kogaki S, Ozono K
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24