Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing.
Conventional gene therapy of hemophilia A relies on the transfer of factor VIII (FVIII; encoded by the F8 gene) cDNA. We carried out spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant FVIII mRNA. A pre-trans-splicing molecule (PTM) corrected endogenous FVIII mRNA in F8 knockout mice with the hemophilia A phenotype, producing sufficient functional FVIII to correct the hemophilia A phenotype. This is the first description of phenotypic correction of a genetic defect by RNA repair in a knockout animal model. Our results indicate the feasibility of using SMaRT to repair RNA for the treatment of genetic diseases.
Chao
Hengjun
H
Department of Medicine, Mt. Sinai School of Medicine, New York, New York 10029, USA.
Mansfield
S Gary
SG
Bartel
Robert C
RC
Hiriyanna
Suja
S
Mitchell
Lloyd G
LG
Garcia-Blanco
Mariano A
MA
Walsh
Christopher E
CE
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D002460:Cell Line; D004195:Disease Models, Animal; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006467:Hemophilia A / Q000235:genetics* / Q000628:therapy; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D017381:Spliceosomes / Q000378:metabolism*
D012313:RNA; D005169:Factor VIII