vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ17.249vavilov-960Research ArticleФизиологическая генетикаPhysiological geneticsКандидатные антиревматические плазмидные конструкции обладают низкой иммуногенностьюCandidate antirheumatic genotherapeutic plasmid constructions have low immunogenicityНепомнящихТ. С.NepomnyashchikhT. S.

Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

ТрегубчакТ. В.TregubchakT. V.

Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

ЯкубицкийС. Н.YakubitskiyS. N.

Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

ТарановО. С.TaranovO. S.

Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

МаксютовР. А.MaksyutovR. A.

Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

ЩелкуновС. Н.ShchelkunovS. N.

Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

snshchel@vector.nsc.ruФедеральное бюджетное учреждение науки Государственный научный центр вирусологии и биотехнологии «Вектор»РоссияState Research Center of Virology and Biotechnology “Vector”Russian Federation201723052017213317322Copyright © Непомнящих Т.С., Трегубчак Т.В., Якубицкий С.Н., Таранов О.С., Максютов Р.А., Щелкунов С.Н., 20172017Непомнящих Т.С., Трегубчак Т.В., Якубицкий С.Н., Таранов О.С., Максютов Р.А., Щелкунов С.Н.Nepomnyashchikh T.S., Tregubchak T.V., Yakubitskiy S.N., Taranov O.S., Maksyutov R.A., Shchelkunov S.N.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/960

Ревматоидный артрит (РА) – тяжелое системное заболевание соединительной ткани с преимущественным поражением суставов по типу хронического прогрессирующего эрозивно-деструктивного полиартрита и внесуставными проявлениями. При РА разрушаются хрящевые поверхности суставов, наблюдаются дегенеративные изменения подхрящевой костной ткани, нарушается подвижность суставов, происходит их деформация. РА страдает около 1 % человеческой популяции. Эффективный способ лечения РА – биологическая терапия с помощью рекомбинантных белков-антагонистов воспалительных цитокинов. Наиболее широко в клинической практике используют ингибиторы фактора некроза опухолей (TNF – tumor necrosis factor) – рекомбинантные TNF-рецепторы и антитела к TNF. Однако эти методы лечения не лишены побочных эффектов. Отмечается повышенная восприимчивость пациентов к инфекционным заболеваниям, увеличивается риск развития онкологических и аутоиммунных патологий. Кроме того, часто происходит снижение эффективности лечения из-за развития иммунного ответа на терапевтический белок. Побочные эффекты связаны с регулярным системным введением больших доз рекомбинантного белка, одним из способов решения этой проблемы может стать генная терапия. Основой новых генотерапевтических препаратов для лечения РА и других заболеваний человека могут стать гены различных вирусов, кодирующие разные иммуномодулирующие белки. Поксвирусы обладают беспрецедентным по сравнению с вирусами других семейств набором генов, продукты которых эффективно модулируют защитные функции организма хозяина. В частности, в геномах ортопоксвирусов есть гены, кодирующие TNF-связывающие белки. Ранее в различных лабораторных моделях было показано, что рекомбинантный TNF-связывающий белок CrmB является эффективным блокатором TNF. Эффективность лечения может снижаться из-за развития иммунного ответа на терапевтический белок, поэтому такие препараты должны обладать низкой иммуногенностью. В настоящей работе показано, что кандидатные антиревматические генотерапевтические плазмидные конструкции, кодирующие поксвирусный TNF-связывающий белок, обладают гораздо меньшей иммуногенностью по сравнению с белковыми препаратами.

Rheumatoid arthritis (RA) is a serious systemic disease of connective tissue, mainly affecting joints but also with different extra-articular manifestations. In the course of RA the degenerative changes occur in cartilage surfaces of affected joints and also in subchondral bone tissue, joints get deformed and lose their mobility. RA affects about 1 % of the global human population. Biological therapy with recombinant protein inhibitors of inflammatory cytokines is an effective and well-accepted treatment of RA. TNF inhibitors such as recombinant receptors or monoclonal antibodies are the most widely used biotherapeutics in clinical practice. However, this treatment has some serious side effects. The patients treated with TNF inhibitors are more susceptible to infection diseases, they are also at higher risk of developing neoplastic or autoimmune disorders. Biotherapeutics become less effective or even lose their efficiency with evoking specific antidrug antibodies. These drawbacks are in general associated with repeated systemic injections of large amounts of recombinant protein required to achieve the therapeutic efficacy. Genetic therapy might provide a good and effective solution. Viral genes coding for immunomodulatory factors could be used to create new gene therapy products to treat RA and other human disease. Poxviruses, as compared to other viral families, have an unprecedentedly rich set of such immunomodulatory genes. In particular, they have genes encoding TNF-binding proteins. Previously in a variety of laboratory models we have shown that recombinant TNF-binding protein CrmB can effectively block TNF. In this work we demonstrated that candidate antirheumatic genotherapeutic plasmid constructions encoding poxviral TNF-binding proteins have low immunogenicity.

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The authors declare that there are no conflicts of interest present.