Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation

被引：78

作者：

Meyer, Kathrin ^{[1
]}

Marquis, Julien ^{[1
]}

Trueb, Judith ^{[1
]}

Nlend, Rachel Nlend ^{[1
]}

Verp, Sonia ^{[2
]}

Ruepp, Marc-David ^{[1
]}

Imboden, Hans ^{[1
]}

Barde, Isabelle ^{[2
]}

Trono, Didier ^{[2
]}

Schuemperli, Daniel ^{[1
]}

机构：

[1] Univ Bern, Inst Cell Biol, CH-3012 Bern, Switzerland

[2] Ecole Polytech Fed Lausanne, Sch Life Sci, Lab Virol & Genet, CH-1015 Lausanne, Switzerland

来源：

HUMAN MOLECULAR GENETICS | 2009年 / 18卷 / 03期

关键词：

MOTOR-NEURON GENE; SMN2; GENE; SURVIVAL; EXPRESSION; ENHANCER; DEFECTS; MICE; DELETIONS; PROTEIN;

D O I：

10.1093/hmg/ddn382

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In spinal muscular atrophy (SMA), the leading genetic cause of early childhood death, the survival motor neuron 1 gene (SMN1) is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilization of exon 7 and the production of functional protein. It has been hypothesized that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evidence for an in vivo improvement of SMA symptoms is lacking. Here, we unambiguously confirm the above hypothesis by showing that a bifunctional U7 snRNA that stimulates exon 7 inclusion, when introduced by germline transgenesis, can efficiently complement the most severe mouse SMA model. These results are significant for the development of a somatic SMA therapy, but may also provide new means to study pathophysiological aspects of this devastating disease.

引用

页码：546 / 555

页数：10

共 35 条

[1] Efficient control of gene expression in the hematopoietic system using a single Tet-on inducible lentiviral vector [J].

Barde, I ;

Zanta-Boussif, MA ;

Paisant, S ;

Leboeuf, M ;

Rameau, P ;

Delenda, C ;

Danos, O .

MOLECULAR THERAPY, 2006, 13 (02) :382-390

[2] Correction of disease-associated exon skipping by synthetic exon-specific activators [J].

Cartegni, L ;

Krainer, AR .

NATURE STRUCTURAL BIOLOGY, 2003, 10 (02) :120-125

[3] Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2 [J].

Cartegni, L ;

Hastings, ML ;

Calarco, JA ;

de Stanchina, E ;

Krainer, AR .

AMERICAN JOURNAL OF HUMAN GENETICS, 2006, 78 (01) :63-77

[4] Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1 [J].

Cartegni, L ;

Krainer, AR .

NATURE GENETICS, 2002, 30 (04) :377-384

[5] A lentiviral vector encoding the human Wiskott Aldrich syndrome protein corrects immune and cytoskeletal defects in WASP knockout mice [J].

Charrier, S ;

Stockholm, D ;

Seye, K ;

Opolon, P ;

Taveau, M ;

Gross, DA ;

Bucher-Laurent, S ;

Delenda, C ;

Vainchenker, W ;

Danos, O ;

Galy, A .

GENE THERAPY, 2005, 12 (07) :597-606

[6]

COBBEN JM, 1995, AM J HUM GENET, V57, P805

[7] The survival motor neuron protein in spinal muscular atrophy [J].

Coovert, DD ;

Le, TT ;

McAndrew, PE ;

Strasswimmer, J ;

Crawford, TO ;

Mendell, JR ;

Coulson, SE ;

Androphy, EJ ;

Prior, TW ;

Burghes, AHM .

HUMAN MOLECULAR GENETICS, 1997, 6 (08) :1205-1214

[8]

Dickson A, 2008, HUM GENE THER, V19, P1307, DOI [10.1089/hum.2008.067, 10.1089/hgt.2008.067]

[9] Quantitative analyses of SMN1 and SMN2 based on real-time LightCycler PCR:: Fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy [J].

Feldkötter, M ;

Schwarzer, V ;

Wirth, R ;

Wienker, TF ;

Wirth, B .

AMERICAN JOURNAL OF HUMAN GENETICS, 2002, 70 (02) :358-368

[10] Neonatal intraperitoneal or intravenous injections of recombinant adeno-associated virus type 8 transduce dorsal root ganglia and lower motor neurons [J].

Foust, Kevin D. ;

Poirier, Amy ;

Pacak, Christina A. ;

Mandel, Ronald J. ;

Flotte, Terence R. .

HUMAN GENE THERAPY, 2008, 19 (01) :61-69

← 1 2 3 4 →