Extrahepatic tissue-targeted gene therapy for phenylketonuria

• Project/Area Number: 20591230
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Jichi Medical University
• Principal Investigator: KUME Akihiro Jichi Medical University, 医学部, 准教授 (10264293)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 小児代謝 / 栄養学 / 遺伝子治療 / フェニルケトン尿症 / 先天代謝異常 / アデノ随伴ウイルス

Research Abstract

The feasibility of muscle-directed gene transfer for the treatment of phenylketonuria (PKU) was investigated. Small-sized promoters were examined for high expression in the context of self-complementary adeno-associated virus (scAAV) vector. Intramuscular injection of a scAAV encoding phenylalanine hydroxylase (PAH) did not show a significant effect in a mouse model of PKU. Simultaneous injection of three scAAV vectors encoding PAH, GTP cyclohydrolase I and 6-pyruvoil tetrahydrobiopterine synthase resulted in a significant, still moderate decrease of blood phenylalanine in PKU mice.

Research Products

• [Journal Article] Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self-complementary adeno-associated virus vector. (2011)
  • Author(s): Yagi H, Ogura T, Mizukami H, Urabe M, Hamada H, Yoshikawa H, Ozawa K, Kume A
  • Journal Title: J Gene Med 13 Pages: 114-122
  • Peer Reviewed
• [Journal Article] Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self-complementary adeno-associated virus vector (2011)
  • Author(s): Yagi H, et al.
  • Journal Title: The Journal of Gene Medicine Volume: 13 Pages: 114-122
  • Peer Reviewed
• [Journal Article] A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson ' s disease. (2010)
  • Author(s): Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K, Kawakami T, Urabe M, Kume A, Sato T, Watanabe E, Ozawa K, Nakano I
  • Journal Title: Mol Ther 18 Pages: 1731-1735
  • Peer Reviewed
• [Journal Article] A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease (2010)
  • Author(s): Muramatsu, S, et al.
  • Journal Title: Molecular Therapy Volume: 18 Pages: 1731-1735
  • Peer Reviewed
• [Journal Article] Systemic delivery of IL-10 by an AAV-vector presents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat. (2009)
  • Author(s): Nomoto T, Okada T, Shimazaki K, Yoshioka T, Nonaka-Sarukawa M, Ito T, Takeuchi K, Katsura KI, Mizukami H, Kume A, Ookawara S, Ikeda U, Katayama Y, Ozawa K
  • Journal Title: Gene Ther 16 Pages: 383-391
  • Peer Reviewed
• [Journal Article] Genomic organization of regions that regulate chicken glycine decarboxylase gene transcription: Physiological and pathological conditions. (2009)
  • Author(s): Kawaguchi H, Okamoto S, Sikdar D, Kume A, Li F, Mohafez OM, Shehata MH, Hiraga K
  • Journal Title: Gene 432 Pages: 7-18
  • Peer Reviewed
• [Journal Article] Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. (2009)
  • Author(s): Uchibori R, Okada T, Ito T, Urabe M, Mizukami H, Kume A, Ozawa K
  • Journal Title: J Gene Med 11 Pages: 373-381
  • Peer Reviewed
• [Journal Article] Kinetics and effect of integrin expression on human CD34+ cells during MLV-derived retroviral transduction with a recombinant fibronectin for stem cell gene therapy. (2009)
  • Author(s): Horiuchi Y, Onodera M, Miyagawa Y, Sato B, Onda K, Katagiri YU, Okita H, Okada M, Otsu M, Kume A, Okuyama T, Fujimoto J, Kuratsuji T, Kiyakawa N
  • Journal Title: Hum Gene Ther 20 Pages: 777-783
  • Peer Reviewed
• [Journal Article] Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy (2009)
  • Author(s): Uchibori R, et al
  • Journal Title: J Gene Med 11 Pages: 373-381
  • Peer Reviewed
• [Journal Article] Kinetics and effect of integrin expression on human CD34+ cells during MLV-derived retroviral transduction with a recombinant fibronectin for stem cell gene therapy (2009)
  • Author(s): Horiuchi Y, et al
  • Journal Title: Hum Gene Ther 20 Pages: 777-783
  • Peer Reviewed
• [Journal Article] Systemic delivery of IL-10 by an AAV-vector presents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat. (2009)
  • Author(s): Nomoto T, et al
  • Journal Title: Gene Therapy 16 Pages: 383-391
  • Peer Reviewed
• [Journal Article] Genomic organization of regions that regulate chicken glycine decarboxylase gene transcription : physiological and pathological conditions. (2009)
  • Author(s): Kawaguchi H, et al
  • Journal Title: Gene 432 Pages: 718-718
  • Peer Reviewed
• [Journal Article] Aden-associated vector-mediated systemic interleukin-10 expression ameliorates hypertensive organ damage in Dahl salt-sensitive rats. (2008)
  • Author(s): Nonaka-Sanikawa M, et al
  • Journal Title: Journal of Gene Medicine 10 Pages: 368-374
  • Peer Reviewed
• [Presentation] Choice of small-sized prpmoter for AAV-mediated factor IX expression in skeletal muscle. (2010)
  • Author(s): Kume A, Yagi H, Mizukami H, Urabe M, Tsukahara T, Ishiwata A, mimuro J, Madoiwa S, Ohmori T, Sakata Y, Ozawa K
  • Organizer: 第16回日本遺伝子治療学会
  • Place of Presentation: 宇都宮
  • Year and Date: 2010-07-01
• [Presentation] Promoter selection for AAV vector-mediated factor IX expression in skeletal muscle (2010)
  • Author(s): Kume A, et al.
  • Organizer: The 13th Annual Meeting of the American Society of Gene and Cell Therapy
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2010-05-21
• [Presentation] Liver-targeted gene therapy with a self-complementary AAV ameliorates brain aminergic deficit in phenylketonuria mice. (2009)
  • Author(s): Kume A, Yagi H, Sanechika S, Ichinose H, Mizukami H, Urabe M, Ozawa K
  • Organizer: XVIIth Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Hannover, Germ any
  • Year and Date: 2009-11-22
• [Presentation] Liver-targeted gene therapy with a self-complementary AAV ameliorates brain aminergic deficit in phenylketonuria mice (2009)
  • Author(s): Kume A, et al
  • Organizer: XVIIth Annual Congress of the European Society of Gene and Cell Therapy
  • Place of Presentation: Hannover, Germany
  • Year and Date: 2009-11-22
• [Presentation] Promoter selection for muscle-directed self-complementary AAV toward hemophilia B gene thearapy. (2009)
  • Author(s): Kume A, Yagi H, Mizukami H, Urabe M, Tsukahara T, Ishiwata A, Mimuro J, Madoiwa S, Ohmori T, Sakata Y, Ozawa K
  • Organizer: 第71回日本血液学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2009-10-23
• [Presentation] Kinetics and defect of integrin expression on human CD34+ cells during MLV-derived retroviral transduction with a recombinant fibronectin for stem cell gene therapy. (2009)
  • Author(s): Horiuchi Y, Onodera M, Miyagawa Y, Sato B, Onda K, Katagiri YU, Okita H, Okada M, Otsu M, Kume A, Okuyaka T, Fujimoto J, Kuratsuji T, Kiyokawa N
  • Organizer: 第15回日本遺伝子治療学会
  • Place of Presentation: 吹田
  • Year and Date: 2009-07-11
• [Presentation] liver-targeted gene therapy with a self-complementary AAV ameliorated brain aminergic deficit in phenylketonuria mice. (2009)
  • Author(s): Yagi H, Sanechika S, Ichinose H, Mizukami H, Ogura T, Urabe M, Hamada H, Yoshikawa K, Ozawa K, Kume A
  • Organizer: 第15回日本遺伝子治療学会
  • Place of Presentation: 吹田
  • Year and Date: 2009-07-11
• [Presentation] Improvement of monoamine metabolism in phenylketonuria mouse brain treated with a self-complementary adeno-associated vector. (2009)
  • Author(s): Yagi H, Sanechika S, Ichinose H, Mizukami H, Ogura T, Urabe M, Hamada H, Yoshikawa H, Ozawa K, Kume A
  • Organizer: American Society of Gene Therapy's 12th Annual Meeting
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2009-05-27
• [Presentation] Promoter selection for AAV vector-mediated factor IX expression in skeletal muscle. (2009)
  • Author(s): Kume A, Yagi H, Mizukami H, Urabe M, Tsukahara T, Ishiwata A, Mimuro J, Madoiwa S, Ohmori T, Sakata Y, Ozawa K
  • Organizer: American Society of Gene Therapy's 13th Annual Meeting
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2009-05-21
• [Presentation] 改良型アデノ随伴ウイルスベクターによるフェニルケトン尿症遺伝子治療 (2009)
  • Author(s): 久米晃啓、八木洋也、小倉剛、水上浩明、卜部匡司、小澤敬也
  • Organizer: 第112回日本小児科学会小児科学会学術集会
  • Place of Presentation: 奈良
  • Year and Date: 2009-04-18
• [Presentation] 自己相補型アデノ随伴ウイルスベクターによるフェニルケトン尿症の遺伝子治療 ? maternal PKUの予防に向けて (2009)
  • Author(s): 八木洋也、水上浩明、小倉剛、濱田洋実、吉川裕之、小澤敬也、久米晃啓
  • Organizer: 第61回日本産婦人科学会学術講演会
  • Place of Presentation: 京都
  • Year and Date: 2009-04-05
• [Presentation] 筋組織を標的とするAAV ベクターを用いた「フェニルケトン尿症」に対する新生仔遺伝子治療の長期的効果 (2009)
  • Author(s): 小倉剛、水上浩明、八木洋也、濱田洋実、吉川裕之、小澤敬也、久米晃啓
  • Organizer: 第61回日本産婦人科学会学術講演会
  • Place of Presentation: 京都
  • Year and Date: 2009-04-05
• [Presentation] Complete retoration of in vivo oxidative capacity for phenylalanine in self-complementary AAV vector-treated phenylketonuria mice. (2008)
  • Author(s): Kume A., et al
  • Organizer: American Society of Gene Therapy 11th Annual Meeting
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2008-05-31