ISSN 10227954, Russian Journal of Genetics, 2016, Vol. 52, No. 6, pp. 543–556. © Pleiades Publishing, Inc., 2016.
Original Russian Text © T.S. Nepomnyashchikh, D.V. Antonets, S.N. Shchelkunov, 2016, published in Genetika, 2016, Vol. 52, No. 6, pp. 625–640.
Arthritis is an inflammatory disease involving the
joints. Presently, more than 100 different forms of
arthritis and relative pathologies are recognized. The
most common forms are rheumatoid arthritis (RA)
and osteoarthritis (OA) [1, 2]. RA is a systemic
autoimmune disease where patients often manifest
antibodies specific to IgG (rheumatoid factor), type II
collagen, cartilage glycoprotein 39, and several other
proteins . RA is characterized by steady progressing
joint and internal organ degeneration, which results in
an early disability and decreased longevity. RA affects
about 70 million people in the world. Most often, the
disease affects the older generation. In contrast to RA,
OA represents a nonsystemic, local disease and it pri
marily results from traumas and agerelated degenera
tive changes in the articular cartilage in large joints .
At present, there no common opinion on the cause
of arthritis development [5, 6]. RA development and
its severity are associated with activation of several
genes, such as HLA, PTPN22, PADI4, CTLA4, and
, and various cytokine genes (TNF, IL1, IL10,
IL18) and their receptors [7, 8]. The information
accumulated at present indicates that arthritis devel
opment involves activation of various factors: genetic,
immunologic, hormonal, and environmental [5, 6, 9].
Cytokines are key modulators of inflammatory and
immune reactions and play a central role in the devel
opment of both RA and OA [2, 8–10]. One of the
major mediators of pathogenesis of these diseases is a
tumor necrosis factor (TNF). Transgenic mice which
express human TNF develop severe erosive arthritis
similar to human rheumatoid arthritis . In mice
(carrying a deletion at the 3'terminal
AUrich regulatory sequence ARE), TNF mRNA sta
bility is increased. This results in the development of
severe polyarthritis and an inflammatory intestinal
disease similar to Crohn’s disease . Owing to the
increased expression of TNF and other proinflamma
tory cytokines such as
, IL6, IFN
, and IL17,
fibroblasts, macrophages, neutrophils, and lympho
cytes are activated in the affected joint and secretion of
matrix metalloproteinase occurs, which finally results
in articular cartilage destruction .
An effective approach to RA and OA therapy is a
treatment with recombinant proteins which interact
with key proinflammatory cytokines and inhibit their
activity [11, 13–16]. Such an approach is called bio
logic therapy. It can produce adverse effects [13, 16].
Therefore, development of gene therapy methods
based on injection of therapeutic genes is an important
aim of biomedicine. Here, we discuss the results of
current research in gene therapy and future prospects
in the field.
OF ARTHRITIS TREATMENT
Interaction of TNF with its cellular receptors can
be potentially inhibited by monoclonal antibodies or
soluble forms of cellular type II TNF receptors
(TNFRII, p75). Such an approach to treatment of
chronic inflammatory diseases was named biologic
therapy. It is appeared to be the most effective among
currently existing therapies .
Clinical studies of biologic antiTNF drugs for RA
treatment started in 1992. The efficacy of antiTNF
therapy was confirmed in 1998 when etanercept
Gene Therapy of Arthritis
T. S. Nepomnyashchikh, D. V. Antonets, and S. N. Shchelkunov
State Research Center of Virusology and Biotechnology “Vector”, Novosibirsk, Koltsovo, 630559 Russia
email: email@example.com, firstname.lastname@example.org
Received September 16, 2015; in final form, November 19, 2015
—Gene therapy can offer a new approach to arthritis treatment which acts at an inflammation site.
Numerous studies show high efficacy of gene therapy in different models of arthritis in humans. Even a single
injection of a recombinant vector results in a stable prolonged expression of a therapeutic gene and a long
term therapeutic effect. In contrast to biologic therapy involving numerous systemic injections of recombi
nant antiinflammatory proteins, gene therapy does not produce systemic side effects. Vectors based on ret
roviruses, adenoviruses, adenoassociated viruses, and recombinant plasmids could provide delivery of target
genes. Of significant importance is the development of noninvasive methods of gene therapy: intranasal and
peroral. The current state of research in arthritis gene therapy is discussed in this review.
: gene therapy, arthritis, cytokines, cytokine antagonists
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