Intra-articular delivery of a herpes simplex virus IL-1Ra gene vector reduces inflammation in a rabbit model of arthritis.
To evaluate the use of HSV-based vectors for arthritis gene therapy we have constructed a first-generation, ICP4 deficient, replication defective herpes simplex virus (HSV) vector (S/0-) and a second-generation HSV vector derivative (T/0-) deficient for the immediate-early genes ICP4, 22 and 27, each carrying a soluble TNF receptor or IL-1 receptor antagonist transgene cassette. A rabbit synovial-fibroblast line in culture, infected by either vector enabled high-level expression of the transgene product. However, following a single intra-articular injection of the vectors into rabbit knee joints, only the second-generation, HSV T/0- vector expressed detectable levels of soluble TNFR in synovial fluid. Synovial lavage fluid from inoculated joints con- tained up to 12 ng/ml of soluble receptor that persisted at detectable, but reduced levels for at least 7 days. When tested in an experimental model of arthritis generated by intra-articular overexpression of interleukin-1beta using retrovirus transduced synovial cells, the HSV T/0- vector expressing the interleukin-1 receptor antagonist was found to inhibit leukocytosis and synovitis significantly. The improved levels and duration of intra-articular transgene expression achieved via HSV-mediated gene delivery suggest that an HSV vector system could be used for therapeutic applications in patients with rheumatoid arthritis (RA) and other joint-related inflammatory diseases.
Oligino
T
T
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Ghivizzani
S
S
Wolfe
D
D
Lechman
E
E
Krisky
D
D
Mi
Z
Z
Evans
C
C
Robbins
P
P
Glorioso
J
J
D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006614:Hindlimb; D007249:Inflammation / Q000628:therapy; D007270:Injections, Intra-Articular; D053590:Interleukin 1 Receptor Antagonist Protein; D007719:Knee Joint; D011817:Rabbits; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D012795:Sialoglycoproteins / Q000235:genetics*; D018139:Simplexvirus / Q000235:genetics*; D013583:Synovial Membrane / Q000276:immunology
D053590:Interleukin 1 Receptor Antagonist Protein; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins