The artificial gene Jazz, a transcriptional regulator of utrophin, corrects the dystrophic pathology in mdx mice.
The absence of the cytoskeletal protein dystrophin results in Duchenne muscular dystrophy (DMD). The utrophin protein is the best candidate for dystrophin replacement in DMD patients. To obtain therapeutic levels of utrophin expression in dystrophic muscle, we developed an alternative strategy based on the use of artificial zinc finger transcription factors (ZF ATFs). The ZF ATF 'Jazz' was recently engineered and tested in vivo by generating a transgenic mouse specifically expressing Jazz at the muscular level. To validate the ZF ATF technology for DMD treatment we generated a second mouse model by crossing Jazz-transgenic mice with dystrophin-deficient mdx mice. Here, we show that the artificial Jazz protein restores sarcolemmal integrity and prevents the development of the dystrophic disease in mdx mice. This exclusive animal model establishes the notion that utrophin-based therapy for DMD can be efficiently developed using ZF ATF technology and candidates Jazz as a novel therapeutic molecule for DMD therapy.
Di Certo
Maria Grazia
MG
Istituto di Neurobiologia e Medicina Molecolare, CNR, IRCCS Fondazione S. Lucia, 00143 Rome, Italy.
Corbi
Nicoletta
N
Strimpakos
Georgios
G
Onori
Annalisa
A
Luvisetto
Siro
S
Severini
Cinzia
C
Guglielmotti
Angelo
A
Batassa
Enrico Maria
EM
Pisani
Cinzia
C
Floridi
Aristide
A
Benassi
Barbara
B
Fanciulli
Maurizio
M
Magrelli
Armando
A
Mattei
Elisabetta
E
Passananti
Claudio
C
D000818:Animals; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D014157:Transcription Factors / Q000235:genetics*; D049411:Utrophin / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers
D016189:Dystrophin; D014157:Transcription Factors; D049411:Utrophin