Abstract
Tumor necrosis factor (TNF)- is produced by cells of the
immune system and is a key mediator in immune and
inflammatory reactions. Through interaction with widely
expressed receptors (TNF receptor 1 and TNF receptor 2),
TNF- is able to orchestrate the expression of a range of
downstream proinflammatory molecules. Over the past decade
novel biologics that inhibit TNF- have been developed as
extremely effective treatments for rheumatoid arthritis.
Structurally, these biologics are antibodies, or TNF receptors
on an antibody backbone that bind TNF- directly and are
delivered to patients by repeated injection. Gene therapy offers
an improved approach to delivering biologics as a single
administration of their encoding genetic material. In the present
study we demonstrate the therapeutic effect of a small
molecular weight dimeric TNF receptor 2 (dTNFR)
constitutively expressed from plasmid DNA, delivered
intramuscularly with electroporation, after disease onset in a
collagen-induced arthritis model. Regulated promoters that
enable the production of a transgene to be controlled are more
suited to the application of gene therapy in the clinic.
Regulated expression of dTNFR from the plasmid pGTRTT was
also therapeutic in the mouse collagen-induced arthritis model
when the inducer doxycycline was also administered, whereas
no therapeutic effect was observed in the absence of
doxycycline. The therapeutic effect of dTNFR expressed from a
constitutive or regulated plasmid was dependent on the degree
of disease activity at the time of DNA injection. The
observations of this study are considered with regard to the
disease model, the magnitude of gene regulation, and the path
to clinical application.
Keywords: arthritis, doxycycline, gene therapy, regulated expression, tumour necrosis factor- SPEXGENO 2010 高通量组织研磨机
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