Adeno-associated virus pseudotype 5 vector improves gene transfer in arthritic joints.
The potential for gene delivery to joints, using recombinant adeno-associated virus (rAAV) vectors for the treatment of rheumatoid arthritis (RA), has received much attention. Different serotypes have different virion shell proteins and, as a consequence, vary in their tropism for diverse tissues. The aim of this study was to compare the transduction efficiency of different AAV serotypes encoding murine secreted alkaline phosphatase (mSEAP) or Escherichia coli beta-galactosidase for intraarticular gene delivery in an experimental model of arthritis. The vectors contained AAV2 terminal repeats flanking the reporter gene in an AAV1, AAV2, or AAV5 capsid, producing the pseudotypes rAAV-2/1, rAAV-2/2, and rAAV-2/5. Left knee joints of mice with collagen-induced arthritis were injected and transgene expression was analyzed by chemiluminescence or direct in situ staining of frozen sections. We show for the first time that intraarticular gene transfer with AAV- 2/5 was far more efficient than with the other serotypes tested. Transgene expression was detectable as early as 7 days after injection, reached a maximum at 21 days, and was stably expressed for at least 130 days, whereas AAV-2/1- and AAV-2/2-mediated expression levels were barely detectable. These findings provide a practical application for future local AAV-mediated gene therapy trials in RA.
Apparailly
F
F
INSERM U475, and Université Montpellier I, 34197 Montpellier, France. appara@montp.inserm.fr
Khoury
M
M
Vervoordeldonk
M J B
MJ
Adriaansen
J
J
Gicquel
E
E
Perez
N
N
Riviere
C
C
Louis-Plence
P
P
Noel
D
D
Danos
O
O
Douar
A-M
AM
Tak
P P
PP
Jorgensen
C
C
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000628:therapy*; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000235:genetics; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D007270:Injections, Intra-Articular; D007596:Joints / Q000187:drug effects / Q000473:pathology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D000469:Alkaline Phosphatase; D001616:beta-Galactosidase