Silencing primary dystonia: Lentiviral-mediated RNA interference therapy for DYT1 dystonia

被引:79
|
作者
Gonzalez-Alegre, P
Bode, N
Davidson, BL
Paulson, HL
机构
[1] Univ Iowa, Carver Coll Med, Dept Neurol, Iowa City, IA 52242 USA
[2] Univ Iowa, Carver Coll Med, Dept Med, Iowa City, IA 52242 USA
来源
JOURNAL OF NEUROSCIENCE | 2005年 / 25卷 / 45期
关键词
dystonia; RNA interference; torsina; dyt1; gene therapy; FIV;
D O I
10.1523/JNEUROSCI.3016-05.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
DYT1 is the most common inherited dystonia. Currently, there are no preventive or curative therapies for this dominantly inherited disease. DYT1 dystonia is caused by a common three-nucleotide deletion in the TOR1A gene that eliminates a glutamic acid residue from the protein torsinA. Recent studies suggest that torsinA carrying the disease-linked mutation, torsinA(Delta E) acts through a dominant-negative effect by recruiting wild-type torsinA [torsinA(wt)] into oligomeric structures in the nuclear envelope. Therefore, suppressing torsinA(Delta E) expression through RNA interference (RNAi) could restore the normal function of torsinA(wt), representing a potentially effective therapy regardless of the biological role of torsinA. Here, we have generated short hairpin RNAs (shRNAs) that mediate allele-specific suppression of torsinA(Delta E) and rescue cells from its dominant-negative effect, restoring the normal distribution of torsinA(wt). In addition, delivery of this shRNA by a recombinant feline immunodeficiency virus effectively silenced torsinA(Delta E) in a neural model of the disease. We further establish the feasibility of this viral-mediated RNAi approach by demonstrating significant suppression of endogenous torsinA in mammalian neurons. Finally, this silencing of torsinA is achieved without triggering an interferon response. These results support the potential use of viral-mediated RNAi as a therapy for DYT1 dystonia and establish the basis for preclinical testing in animal models of the disease.
引用
收藏
页码:10502 / 10509
页数:8
相关论文
共 50 条
  • [21] DYT1 mutation in Korean dystonia patients
    Ahn, TB
    Im, JH
    Kim, KB
    Ko, SB
    Jeon, BS
    MOVEMENT DISORDERS, 2002, 17 : S285 - S285
  • [22] Functional brain networks in DYT1 dystonia
    Eidelberg, D
    Moeller, JR
    Antonini, A
    Kazumata, K
    Nakamura, T
    Dhawan, V
    Spetsieris, P
    deLeon, D
    Bressman, SB
    Fahn, S
    ANNALS OF NEUROLOGY, 1998, 44 (03) : 303 - 312
  • [23] Investigating DYT1 in a Taiwanese dystonia cohort
    Wu, Meng-Chen
    Chang, Yung-Yee
    Chen, Ying-Fa
    Lan, Min-Yu
    Chen, Pei-Lung
    Tai, Chun-Hwei
    Lin, Chin-Hsien
    JOURNAL OF THE FORMOSAN MEDICAL ASSOCIATION, 2022, 121 (01) : 375 - 380
  • [24] Molecular basis of DYT1 and DYT6 primary dystonia in Indian patients
    Subhajit Giri
    Arindam Biswas
    Shyamal Kumar Das
    Kunal Ray
    Jharna Ray
    Molecular Cytogenetics, 7 (Suppl 1)
  • [25] Genetics and Pathophysiology of Primary Dystonia with Special Emphasis on DYT1 and DYT5
    Segawa, Masaya
    Nomura, Yoshiko
    SEMINARS IN NEUROLOGY, 2014, 34 (03) : 306 - 311
  • [26] Developments in the molecular biology of DYT1 dystonia
    Walker, RH
    Shashidharan, P
    MOVEMENT DISORDERS, 2003, 18 (10) : 1102 - 1107
  • [27] The Cognitive Features of Idiopathic and DYT1 Dystonia
    Jahanshahi, Marjan
    Torkamani, Mariam
    MOVEMENT DISORDERS, 2017, 32 (10) : 1348 - 1355
  • [28] A role for cerebellum in the hereditary dystonia DYT1
    Fremont, Rachel
    Tewari, Ambika
    Angueyra, Chantal
    Khodakhah, Kamran
    ELIFE, 2017, 6
  • [29] A2A receptors in mouse model of DYT1 primary dystonia
    Sancesario, Giuseppe
    D'Angelo, Vincenza
    Bernardi, Giorgio
    Fusco, Francesca
    Martella, Giuseppina
    Paldino, Emanuela
    Cardarelli, Silvia
    Giorgi, Mauro
    Mercuri, Nicola
    Pisani, Antonio
    JOURNAL OF THE NEUROLOGICAL SCIENCES, 2021, 429
  • [30] Lentiviral-mediated RNA interference
    Abbas-Terki, T
    Blanco-Bose, W
    Déglon, N
    Pralong, W
    Aebischer, P
    HUMAN GENE THERAPY, 2002, 13 (18) : 2197 - 2201