AAV vector-mediated microdystrophin expression in a relatively small percentage of mdx myofibers improved the mdx phenotype

被引:88
作者
Yoshimura, M
Sakamoto, M
Ikemoto, M
Mochizuki, Y
Yuasa, K
Miyagoe-Suzuki, Y
Takeda, S
机构
[1] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mol Therapy, Kodaira, Tokyo 1878502, Japan
[2] Univ Tokyo, Grad Sch Med, Dept Neurol, Div Neurosci, Tokyo 1138655, Japan
关键词
Duchenne muscular dystrophy; gene therapy; adeno-associated virus vector; dystrophin; microdystrophin; skeletal muscle; mdx mouse; hypertrophy;
D O I
10.1016/j.ymthe.2004.07.025
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Duchenne muscular dystrophy (DMD) is a lethal disorder of skeletal muscle caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vector-mediated gene therapy is a promising approach to the disease. Although a rod-truncated microdystrophin gene has been proven to ameliorate dystrophic phenotypes, the level of microdystrophin expression required for effective gene therapy by an AAV vector has not been determined yet. Here, we constructed a recombinant AAV type 2 vector, AAV2-MCKDeltaCS1, expressing microdystrophin (DeltaCS1) under the control of a muscle-specific MCK promoter and injected it into TA muscles of 10-day-old and 5-week-old mdx mice. AAV2-MCKDeltaCS1-mediated gene transfer into 5-week-old mdx muscle resulted in extensive and long-term expression of microdystrophin and significantly improved force generation. Interestingly, 10-day-old injected muscle expressed microdystrophin in a limited number of myofibers but showed hypertrophy of microdystrophin-positive muscle fibers and considerable recovery of contractile force. Thus, we concluded that AAV2-MCKDeltaCS1 could be a powerful tool for gene therapy of DMD.
引用
收藏
页码:821 / 828
页数:8
相关论文
共 28 条
  • [1] HUMAN DYSTROPHIN EXPRESSION IN MDX MICE AFTER INTRAMUSCULAR INJECTION OF DNA CONSTRUCTS
    ACSADI, G
    DICKSON, G
    LOVE, DR
    JANI, A
    WALSH, FS
    GURUSINGHE, A
    WOLFF, JA
    DAVIES, KE
    [J]. NATURE, 1991, 352 (6338) : 815 - 818
  • [2] In vivo targeted repair of a point mutation in the canine dystrophin gene by a chimeric RNA/DNA oligonucleotide
    Bartlett, RJ
    Stockinger, S
    Denis, MM
    Bartlett, WT
    Inverardi, L
    Le, TT
    Man, NT
    Morris, GE
    Bogan, DJ
    Metcalf-Bogan, J
    Kornegay, JN
    [J]. NATURE BIOTECHNOLOGY, 2000, 18 (06) : 615 - 622
  • [3] Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice
    Barton, ER
    Morris, L
    Musaro, A
    Rosenthal, N
    Sweeney, HL
    [J]. JOURNAL OF CELL BIOLOGY, 2002, 157 (01) : 137 - 147
  • [4] Functional improvement of dystrophic muscle by myostatin blockade
    Bogdanovich, S
    Krag, TOB
    Barton, ER
    Morris, LD
    Whittemore, LA
    Ahima, RS
    Khurana, TS
    [J]. NATURE, 2002, 420 (6914) : 418 - 421
  • [5] CHARACTERIZATION OF DYSTROPHIN IN CARRIERS OF DUCHENNE MUSCULAR-DYSTROPHY
    CLERK, A
    RODILLO, E
    HECKMATT, JZ
    DUBOWITZ, V
    STRONG, PN
    SEWRY, CA
    [J]. JOURNAL OF THE NEUROLOGICAL SCIENCES, 1991, 102 (02) : 197 - 205
  • [6] Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length dystrophin
    DelloRusso, C
    Scott, JM
    Hartigan-O'Connor, D
    Salvatori, G
    Barjot, C
    Robinson, AS
    Crawford, RW
    Brooks, SV
    Chamberlain, JS
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (20) : 12979 - 12984
  • [7] Dynamin is required for recombinant adeno-associated virus type 2 infection
    Duan, DS
    Li, Q
    Kao, AW
    Yue, YP
    Pessin, JE
    Engelhardt, JF
    [J]. JOURNAL OF VIROLOGY, 1999, 73 (12) : 10371 - 10376
  • [8] VERY MILD MUSCULAR-DYSTROPHY ASSOCIATED WITH THE DELETION OF 46-PERCENT OF DYSTROPHIN
    ENGLAND, SB
    NICHOLSON, LVB
    JOHNSON, MA
    FORREST, SM
    LOVE, DR
    ZUBRZYCKAGAARN, EE
    BULMAN, DE
    HARRIS, JB
    DAVIES, KE
    [J]. NATURE, 1990, 343 (6254) : 180 - 182
  • [9] Adeno-associated virus vector gene transfer and sarcolemmal expression of a 144 kDa micro-dystrophin effectively restores the dystrophin-associated protein complex and inhibits myofibre degeneration in nude/mdx mice
    Fabb, SA
    Wells, DJ
    Serpente, P
    Dickson, G
    [J]. HUMAN MOLECULAR GENETICS, 2002, 11 (07) : 733 - 741
  • [10] Recombinant adeno-associated virus for muscle directed gene therapy
    Fisher, KJ
    Jooss, K
    Alston, J
    Yang, YP
    Haecker, SE
    High, K
    Pathak, R
    Raper, SE
    Wilson, JM
    [J]. NATURE MEDICINE, 1997, 3 (03) : 306 - 312