Perinatal gene therapy for severe genetic diseases

2012 Fiscal Year Final Research Report

• Project/Area Number: 22390212
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nippon Medical School
• Principal Investigator: SHIMADA Takashi 日本医科大学, 大学院・医学研究科, 教授 (20125074)
• Co-Investigator(Renkei-kenkyūsha): MIYAKE Koichi 日本医科大学, 医学部, 准教授 (90267211) ; MIGITA Makoto 日本医科大学, 医学部, 准教授 (50256963) ; WATANABE Atsushi 日本医科大学, 医学部, 准教授 (10307952)
• Project Period (FY): 2010 – 2012
• Keywords: 遺伝子 / 遺伝子治療 / 遺伝病

Research Abstract

We investigated the feasibility of prenatal/neonatal gene therapy of both metachromatic leukodystrophy (MLD) and hypophosphatasia (HPP) model mice using adeno-associated viral (AAV) vectors. After intravenous injection of AAV vector into neonatal MLD mice, global gene transfer into the brain across the BBB and long term gene expression without immune reaction were detected. Significant improvement of neurological symptoms was observed after treatment. The fetuses of HPP mice underwent transuterine intraperitoneal injection of AAV vector. Live-born mice showed improved mineralization, phenotypic correction and prolonged survival. These data demonstrated that systemic injection of AAV vector in the perinatal period is an effective strategy for the treatment of severe genetic diseases such as MLD and HPP.

Research Products

• [Journal Article] Direct Comparison of Administration Routes for AAV8-Mediated Ocular Gene Therapy. (2013)
  • Author(s): Igarashi, T., Miyake, K., Asakawa, N., Miyake, N., Shimada, T., Takahashi, H.
  • Journal Title: Current Eye Res. Volume: (in press)
• [Journal Article] 5'-HS4 core insulator blocks promoter interference in the lentivirus vector including the MSCV-U3 and EF1α double internal promoters. (2013)
  • Author(s): Uchida, N., Hanawa, H., Yamamoto, M., Shimada, T.
  • Journal Title: Hum. Gene Ther. Volume: (in press)
• [Journal Article] AAV-8 vector expressing IL-24 efficiently suppresses tumor growth mediated by specific mechanisms inMLL/AF4-positive ALL model mice. (2012)
  • Author(s): Tamai, H., Miyake, K., Yamaguchi, H., Takatori, M., Dan, K., Inokuchi, K., Shimada, T.
  • Journal Title: Blood Volume: 119 Pages: 64-71
• [Journal Article] Successful gene therapy in utero for lethal murine hypophosphatasia. (2012)
  • Author(s): Sugano, H., Matsumoto, T., Miyake, K., Watanabe, A., Iijima, O., Migita, M., Narisawa, S., Millan, J.L., Fukunaga, Y., Shimada, T.
  • Journal Title: Hum. Gene Ther. Volume: 23 Pages: 399-406
• [Journal Article] Serotype-independent method of recombinant adeno-associated virus (AAV) vector production and purification. (2012)
  • Author(s): Miyake, K., Miyake, N., Yamazaki, Y., Shimada, T., Hirai, Y.
  • Journal Title: J Nippon Med Sch. Volume: 79 Pages: 394-402
• [Journal Article] Prolonged survival and phenotypic correction of Akp2-/- hypophosphatasia mice by lentiviral gene therapy. (2011)
  • Author(s): Yamamoto, S., Orimo, H., Matsumoto, T., Iijima, O., Narisawa, S., Maeda, T., Millan, J., Shimada, T.
  • Journal Title: J. Bone Miner. Res. Volume: 26 Pages: 135-142
• [Journal Article] A lentiviral strategy for highly efficient retrograde gene transfer by pseudotyping with fusion envelope glycoprotein. (2011)
  • Author(s): Kato, S., Kobayashi, K., Inoue, K., Kuramochi, M., Okada, T., Yaginuma, H., Morimoto, K., Shimada, T., Takada, M., Kobayashi, K.
  • Journal Title: Hum. Gene Ther. Volume: 22 Pages: 197-206
• [Journal Article] In Vivo Application of an RNAi Strategy for the Selective Suppression of aMutant Allele. (2011)
  • Author(s): Kubodera, T., Yamada, H., Anzai, M., Ohira, S., Yokota, S., Hirai, Y., Mochizuki, H., Shimada, T., Mitani, T., Mizusawa, H., Yokota, T.
  • Journal Title: Hum. Gene Ther. Volume: 22 Pages: 27-34
• [Journal Article] Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers. (2011)
  • Author(s): Watanabe A, Karasugi T, Sawai H, Banyar Tang Naing, Ikegawa S, Orimo H, Shimada S.
  • Journal Title: J Hum Genet Volume: 56 Pages: 166-168
• [Journal Article] Intraperitoneal AAV9-shRNA inhibits target expression in neonatal skeletal and cardiac muscles. (2011)
  • Author(s): Mayra, A., Tomimitsu, H., Kubodera, T., Kobayashi, M., Piao, W., Sunaga, F., Hirai, Y., Shimada, T., Mizusawa, H., Yokota, T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 405 Pages: 204-209
• [Journal Article] Global gene transfer into the CNS across the BBB after neonatal systemic delivery of single-stranded AAV vectors. (2011)
  • Author(s): Miyake, N., Miyake, K., Yamamoto, M., Hirai, Y., Shimada, T.
  • Journal Title: Brain Res. Volume: 1389 Pages: 19-26
• [Journal Article] Rescue of Severe Infantile Hypophosphatasia Mice by AAV Mediated Sustained Expression of Soluble Alkaline Phosphatase. (2011)
  • Author(s): Matsumoto, T., Miyake, K., Yamamoto, S., Orimo, H., Miyake, N., Odagaki, Y.,Adachi, K., Iijima, O., Narisawa, S., Millan, J.L., Fukunaga, Y., Shimada, T.
  • Journal Title: Hum. Gene Ther. Volume: 22 Pages: 1355-1364
• [Journal Article] Direct comparison of four adeno-associated virus serotypes in mediating the production of anti-angiogenic proteins in mouse muscle. (2011)
  • Author(s): Isotani, M., Miyake, K., Miyake, N., Hirai, Y., Shimada, T.
  • Journal Title: Cancer Invest. Volume: 29 Pages: 353-359
• [Journal Article] Neuron-Specific Gene Transfer through Retrograde Transport of Lentiviral Vector Pseudotyped with a Novel Type of Fusion Envelope Glycoprotein. (2011)
  • Author(s): Kato, S., Kuramochi, M., Takasumi, K., Kobayashi, K., Inoue, K., Takahara, D., Hitoshi, S., Takenaka, K., Shimada, T., Takada, M., Kobayashi, K.
  • Journal Title: Hum. Gene Ther. Volume: 22 Pages: 1511-1523
• [Journal Article] Adeno-associated viral vector-mediated gene transduction in mesencephalic slice culture. (2011)
  • Author(s): Nihira, T., Yasuda, T., Hirai, Y., Shimada, T., Mizuno, Y., Mochizuki, H.
  • Journal Title: J Neurosci Methods. Volume: 201 Pages: 55-60
• [Journal Article] Overexpression of GDNF in the Uninjured DRG Exerts Analgesic Effects on Neuropathic Pain Following Segmental Spinal Nerve Ligation in Mice. (2011)
  • Author(s): Takasu, K., Sakai, A., Hanawa, H., Shimada, T., Suzuki, H.
  • Journal Title: J. Pain Volume: 12 Pages: 1130-1139
• [Journal Article] Hematopoiesis in regenerated bone marrow within hydroxyapatite scaffold. (2010)
  • Author(s): Fujita, A., Migita, M., Ueda, T., Ogawa, R., Fukunaga, Y., Shimada, T.
  • Journal Title: Pediatr. Res. Volume: 68 Pages: 35-40
• [Journal Article] Adeno-associated vector (type8)-mediated expression of soluble Flt-1 efficiently inhibits neovascularization in a murine choroidalneovascularization model. (2010)
  • Author(s): Igarashi, T., Miyake, K., Masuda, I., Takahashi, H., Shimada, T.
  • Journal Title: Hum. Gene Ther. Volume: 21 Pages: 631-637
• [Journal Article] Successful treatment of metachromatic leukodystrophy using bone marrow transplantation of HoxB4 overexpressing cells. (2010)
  • Author(s): Miyake, N., Miyake, K., Karlsson, S., Shimada, T.
  • Journal Title: Mol. Ther. Volume: 18 Pages: 1373-1378
• [Journal Article] Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway. (2010)
  • Author(s): Yasuniwa, Y., Izumi, H., Wang, K-Y., Shimajiri, S., Sasaguri, Y., Kawai, K., Kasai, H., Shimada, T., Miyake,. K., Kashiwagi, E., Hirano, G., Kidani, A.,Akiyama, M., Han, B., Wu, Y., Ieiri, I., Higuchi, S., Kohno, K.
  • Journal Title: PloS ONE Volume: 5 Pages: e15330
• [Journal Article] Cyclical mechanical stretch enhances degranulation and IL-4 secretion in RBL-2H3 mast cells.
  • Author(s): Komiyama, H., Miyake, K., Asai, K., Mizuno, K., Shimada, T.
  • Journal Title: Cell Biochem. Function Volume: (in press)
• [Presentation] AAV9 mediated gene therapy of MLD model mice. (2012)
  • Author(s): Miyake, N., Miyake, K., Sakai, A., Yamamoto, M., Endo, A., Suzuki, H., Shimada, T.
  • Organizer: 20th Annual Meeting of the European Society of Gene & Cell Therapy.
  • Place of Presentation: Versailles, France
  • Year and Date: 20121000
• [Presentation] Gene therapy for lethalmurine hyopophosphatasia. (2012)
  • Author(s): Shimada T
  • Organizer: 6th International Alkaline Phosphatase And Hypophosphatasia Symposium.
  • Place of Presentation: Huningue, Alsace, France
  • Year and Date: 20120516-19
• [Presentation] Gene therapy of adult MLD model mice by intrathecal administration of type 9 AAV vector. (2012)
  • Author(s): Miyake, N., Miyake, K., Sakai, A., Yamamoto, M., Endo, A., Suzuki, H., Shimada, T.
  • Organizer: 15th Annual Meeting of the American Society of Gene & Cell Therapy.
  • Place of Presentation: Philadelphia, Pennsylvania
  • Year and Date: 20120500
• [Presentation] A single injection of AAV-8 vector expressing IL-24 efficiently suppressestumor growth mediated by multiple anti-tumor mechanisms in MLL/AF4 positive ALL model mice. (2011)
  • Author(s): Tamai, H., Miyake, K., Yamaguchi, H., Inokuchi, K., Shimada, T., Dan, K.
  • Organizer: 2011European Hematology AssociationCongress.
  • Place of Presentation: London
  • Year and Date: 20110600
• [Presentation] Successful Treatment of Hypophosphatasia Model Mice by a Single Intramuscular Injection of AAV Type 8 Vector Expressing Tissue-Nonspecific Alkaline Phosphatase. (2011)
  • Author(s): Matsumoto, T., Miyake, K., Miyake, N., Orimo, H., Narisawa, S., Millan, J.L. Fukunaga, Y., Shimada. T.
  • Organizer: 14th Annual Meeting of the American Society of Gene & Cell Therapy.
  • Place of Presentation: Seattle, WA
  • Year and Date: 20110500
• [Presentation] Fetal Gene Therapy for Lethal Murine Hypophosphatasia. (2011)
  • Author(s): Sugano, H., Matsumoto, T., Miyake, K., Watanabe, A., Narisawa, S.,Millan, J.L., Fukunaga, Y., Shimada, T.
  • Organizer: 14th Annual Meeting of the American Society of Gene & Cell Therapy.
  • Place of Presentation: Seattle, WA
  • Year and Date: 20110500
• [Presentation] Direct Comparison of Administration Routes for AAV 8 Mediated Ocular Gene Therapy. (2011)
  • Author(s): Igarashi, T., Miyake, K., Asakawa, N., Shimada, T., Takahashi, H.
  • Organizer: 14th Annual Meeting of the American Society of Gene & Cell Therapy.
  • Place of Presentation: Seattle, WA
  • Year and Date: 20110500
• [Presentation] IntrathecalAdministration of Type 9 AAV Vector Expressing Arylsulfatase A Is Effective for Reduction of Sulfatide Storage but Not for Correction of Neurological Deficits in Adult Metachromatic Leukodystrophy Model Mice with Overt Neurological Symptoms. (2011)
  • Author(s): Miyake, N., Miyake, K., Sakai, A., Yamamoto, M., Endo, A., Suzuki, H., Shimada, T.
  • Organizer: 14th Annual Meeting of the American Society of Gene & Cell Therapy.
  • Place of Presentation: Seattle, WA
  • Year and Date: 20110500
• [Presentation] Systemic injection of AAV type 9 in utero facilitates global gene expression in the CNS. (2010)
  • Author(s): Sugano H, Miyake N, Endo A , Miyake K , Shimada T.
  • Organizer: International workshop of lysosomal storage disease.
  • Place of Presentation: Prague, Czech
  • Year and Date: 20101200
• [Presentation] Systemic injection of AAV type 9 in utero facilitates global gene expression in the CNS. (2010)
  • Author(s): Sugano H, Miyake N, Endo A , Miyake K , Shimada T.
  • Organizer: 18th European Society of Gene and Cell Therapy Annual Congress.
  • Place of Presentation: Milano,Italy
  • Year and Date: 20101000
• [Presentation] Global gene transfer in the CNS and phenotypic correction of MLD model mice by systemic neonatal injection of serotype 9 AAV vector. (2010)
  • Author(s): Miyake N, Miyake K, Asakawa N, Okabe M, Yamamoto M, Shimada T.
  • Organizer: European Human Genetics Conference 2010.
  • Place of Presentation: Gothenburg, Sweden
  • Year and Date: 20100600
• [Presentation] Long term correction of biochemical and neurological abnormalities of MLD model mice by systemic neonatal injection of serotype 9. (2010)
  • Author(s): Miyake N, Miyake K, Asakawa N, Yamamoto M, Shimada T.
  • Organizer: 13th Annual Meeting of the American Society of Gene & Cell Therapy.
  • Place of Presentation: Washington, DC
  • Year and Date: 20100500
• [Presentation] AAV Vector Mediated Enzyme Replacement Therapy of Hypophosphatasia (HPP) Model Mice. (2010)
  • Author(s): Matsumoto T, Yamamoto S, Orimo H, Miyake K, Miyake N, Narisawa S, Millan JL, Fukunaga Y, Shimada T.
  • Organizer: 13th Annual Meeting of the AmericanSociety of Gene & Cell Therapy.
  • Place of Presentation: Washington, DC
  • Year and Date: 20100500
• [Presentation] Genotype frequency of 1559T deletion (1559delT) in the TNSALP gene and clinical significance of hypophoshatasia in Japan. (2010)
  • Author(s): Watanabe A, Naing BT, Sawai H, Karasugi T, Kondo H, Ikegawa S, Orimo H, Shimada T.
  • Organizer: 2010 ACMG Annual Clinical Genetics Meeting.
  • Place of Presentation: Albuquerque, NM
  • Year and Date: 20100300
• [Book] Development of muscle directed systemic cancer gene therapy. (2013)
  • Author(s): Miyake, K., Shimada, T.
  • Publisher: GeneTherapy/Book 1 (Edited by MingWei) InTech.
• [Book] Prenatal diagnosis of severe perinatal (lethal) hypophosphatasia. (2012)
  • Author(s): Watanabe, A., Orimo, H., Takeshita, T., Shimada, T.
  • Publisher: Prenatal Diagnosis - Morphology Scan and Invasive Methods (Edited by Richard Choy) InTech.
• [Book] Development and application of HIVvectors pseudotyped with HIV envelopes. (2011)
  • Author(s): Miyake, K., Shimada, T.
  • Total Pages: 355-370
  • Publisher: Viral Gene Therapy (Edited by Ke Xu)