Novel adeno-associated viral vector delivering the utrophin gene regulator jazz counteracts dystrophic pathology in mdx mice.
Over-expression of the dystrophin-related gene utrophin represents a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). The strategy is based on the ability of utrophin to functionally replace defective dystrophin. We developed the artificial zinc finger transcription factor "Jazz" that up-regulates both the human and mouse utrophin promoter. We observed a significant recovery of muscle strength in dystrophic Jazz-transgenic mdx mice. Here we demonstrate the efficacy of an experimental gene therapy based on the systemic delivery of Jazz gene in mdx mice by adeno-associated virus (AAV). AAV serotype 8 was chosen on the basis of its high affinity for skeletal muscle. Muscle-specific expression of the therapeutic Jazz gene was enhanced by adding the muscle α-actin promoter to the AAV vector (mAAV). Injection of mAAV8-Jazz viral preparations into mdx mice resulted in muscle-specific Jazz expression coupled with up-regulation of the utrophin gene. We show a significant recovery from the dystrophic phenotype in mAAV8-Jazz-treated mdx mice. Histological and physiological analysis revealed a reduction of fiber necrosis and inflammatory cell infiltration associated with functional recovery in muscle contractile force. The combination of ZF-ATF technology with the AAV delivery can open a new avenue to obtain a therapeutic strategy for treatment of DMD.
Institute of Cell Biology and Neurobiology CNR, IRCCS Fondazione Santa Lucia, Rome, Italy.
Georgios
G
Strimpakos
Nicoletta
N
Corbi
Cinzia
C
Pisani
Maria Grazia
MG
Di Certo
Annalisa
A
Onori
Siro
S
Luvisetto
Cinzia
C
Severini
Francesca
F
Gabanella
Lucia
L
Monaco
Elisabetta
E
Mattei
Claudio
C
Passananti
D000199:Actins / Q000235:genetics; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009336:Necrosis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics; D020127:Recovery of Function; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D049411:Utrophin / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics
C541116:ACTA2 protein, human; D000199:Actins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C483600:Utrn protein, mouse; D049411:Utrophin; C000589674:Vp16-Jazz protein