Mx1 and IP-10: biomarkers to measure IFN-beta activity in mice following gene-based delivery.
Recombinant interferon-beta (IFN-beta) protein is used successfully for the treatment of multiple sclerosis (MS). Gene therapy might be an alternative approach to overcome drawbacks occurring with IFN-beta protein therapy. A critical issue in developing a new approach is detection of biologically active IFN-beta in preclinical models. The goal of the present study was to determine if Mx1 and IP-10, which are known to be activated after IFN-beta treatment in humans, can be used as biomarkers in mice. In three in vivo experiments, the correlation between different methods of murine IFN-beta (MuIFN-beta) delivery and biomarker induction was studied: (1) bolus protein delivery by intravenous (i.v.) or intramuscular (i.m.) injection, (2) gene-based delivery of IFN- beta by i.m. injection of plasmid DNA, followed by electroporation, and (3) gene-based delivery of IFN-beta by i.m. injection of adenovirus-associated type 1 (AAV1). Short-term induction of Mx1 mRNA and IP-10 was observed after treatment with bolus MuIFN-beta protein. Long-term induction of both biomarkers was observed after IFN-beta plasmid DNA delivery or when AAV1 was used as the vector. The experiments demonstrate that gene-based delivery provides sustained levels of IFN-beta compared with bolus protein injection and that Mx1 RNA and IP-10 can be used to monitor biologically active circulating plasma MuIFN-beta protein in mice.
Petry
Harald
H
Department of Gene Therapy, Berlex Biosciences, Richmond, CA 94806, USA. Harald_Petry@berlex.com
Cashion
Linda
L
Szymanski
Paul
P
Ast
Oliver
O
Orme
Ann
A
Gross
Cynthia
C
Bauzon
Maxine
M
Brooks
Alan
A
Schaefer
Caralee
C
Gibson
Heather
H
Qian
Husheng
H
Rubanyi
Gabor M
GM
Harkins
Richard N
RN
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D018274:Electroporation; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007267:Injections; D016899:Interferon-beta / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064547:Myxovirus Resistance Proteins; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
D015415:Biomarkers; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D016899:Interferon-beta; D019204:GTP-Binding Proteins