Arthritis and gene therapy

The nonsteroidal anti-inflammatory drug (NSAID) Celecoxib (Celebrex(®)) received Food and Drug Administration (FDA) approval in 1998 for treatment of osteoarthritis and rheumatoid arthritis, and in recent years, its use has been extended to various types of malignancies, such as breast, colon, and urinary cancers. To maintain the survival of malignant B cells, non-Hodgkin's Lymphoma (NHL) is highly dependent on inflammatory microenvironment, and is inhibited by celecoxib. Celecoxib hinders tumor growth interacting with various apoptotic genes, such as cyclooxygenase-2 (Cox-2), B-cell lymphoma 2 (Bcl-2) family, phosphor-inositide-3 kinase/serine-threonine-specific protein kinase (PI3K/Akt), and inhibitors of apoptosis proteins (IAP) family...

BACKGROUND: Human polymorphisms with derived alleles that are protective against disease may provide powerful translational opportunities. Here we report a method to identify such candidate polymorphisms and apply it to common non-synonymous SNPs (nsSNPs) associated with common diseases. Our study also sought to establish which of the identified protective nsSNPs show evidence of positive selection, taking this as indirect evidence that the protective variant has a beneficial effect on phenotype...

In rheumatoid arthritis (RA), the proliferation of fibroblast-like synoviocytes (FLS) is the cause of chronic inflammation in joints and of joint damage. Delivery of the pro-apoptotic gene PUMA to FLS via human adenovirus type 5 (HAdV5) vectors has been tested as a therapeutic approach, but efficiency is hampered by low transduction, as FLS do not express HAdV5 receptors on the cell surface. Here we show that efficient transduction of PUMA in FLS can be achieved by conjugating HAdV5 to a baculovirus, which binds to the cell surface via the envelope glycoprotein Gp64...

New therapies, recent pathophysiological findings, and updated guidelines combined to create compelling presentations at the Skin Disease Education Foundation's 41st Annual Hawaii Dermatology Seminar™. This educational supplement summarizes the highlights of clinical sessions presented during this CME/CE conference. A growing understanding of the biology of psoriasis has facilitated the development of increasingly efficacious medications. Skin clearance used to be regarded as an impractical goal for psoriasis therapy...

OBJECTIVES: Gliostatin (GLS) has angiogenic and arthritogenic activities and enzymatic activity as thymidine phosphorylase. Aberrant GLS production has been observed in the synovial membranes of patients with rheumatoid arthritis (RA). Matrix metalloproteinases (MMPs) are involved in joint destruction. Promoters of GLS and some MMP genes contain Sp1 binding sites. We examined the inhibitory effect of the Sp1 inhibitor mithramycin on GLS-induced GLS and MMP expression in cultured fibroblast-like synoviocytes (FLSs)...

OBJECTIVE: To investigate the potential of the baseline gene expression in the whole blood of disease-modifying anti-rheumatic drug-naïve rheumatoid arthritis (RA) patients for predicting the response to methotrexate (MTX) treatment. METHODS: Twenty-six control subjects and 40 RA patients were examined. Clinical, immunological and radiographic parameters were assessed before and after 24 months of follow-up. The gene expressions in the whole blood were measured using real-time reverse transcription polymerase chain reaction...

The Ras family of GTPases plays an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for T-cell receptor activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from rheumatoid arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization...

BACKGROUND: Methotrexate is endorsed to be used as first-line treatment in rheumatoid arthritis (RA). However, a large proportion of patients need additional treatment with a biological disease-modifying anti-rheumatic drug (DMARD) to adequately suppress their disease activity. A better understanding of genotypes could help to distinguish between patients with different pathogenic mechanisms. The aim of this study was therefore to identify networks of genes within DMARD-naive early RA patients associated with achieving sustained drug-free remission (sDFR) after initiating tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy...

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. This study focuses on identifying new associations among oligoarticular and polyarticular rheumatoid factor negative (RF(-) ) JIA, which are clinically similar and the most prevalent JIA disease subtypes. METHODS: Three cohorts totaling 2,751 oligoarticular and polyarticular RF(-) JIA cases were genotyped on the Affymetrix Genome-Wide SNP Array 6...

BACKGROUND: Mesenchymal stem cells (MSCs) represent an important source for cell therapy in regenerative medicine. MSCs have shown promising results for repair of damaged tissues in various degenerative diseases in animal models and also in human clinical trials. However, little is known about the factors that could enhance the migration and tissue-specific engraftment of exogenously infused MSCs for successful regenerative cell therapy. Previously, we have reported that interleukin-3 (IL-3) prevents bone and cartilage damage in animal models of rheumatoid arthritis and osteoarthritis...

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting approximately 2% to 3% of the population globally, and is characterized by both peripheral articular manifestations and axial skeletal involvement. Conventional therapies for PsA have not been fully satisfactory, though natural products (NPs) have been shown to be highly effective and represent important treatment options for psoriasis. PsA is a multigenic autoimmune disease with both environmental and genetic factors contributing to its pathogenesis...

The t(3;21)(q26.2;q22) translocation is a rare chromosomal abnormality exhibited almost exclusively in therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) or in the blastic crisis phase of chronic myelogenous leukemia, which results in the fusion of the runt related transcription factor 1 (RUNX1, also called AML1) gene at 21q22 to the myelodysplasia syndrome 1 (MDS1)-ecotropic virus integration site 1 (EVI1) complex locus (MECOM) at 3q26.2, generating various fusion transcripts, including AML1/MDS1/EVI1 (AME)...

Autoimmunity arises when highly active immune responses are developed against the tissues or substances of one's own body. It is one of the most prevalent disorders among the old-age population with prospects increasing with age. The major cause of autoimmunity and associated diseases is the dysregulation of host immune surveillance. Impaired repairment of immune system and apoptosis regulation can be seen as major landmarks in autoimmune disorders such as the mutation of p53 gene which results in rheumatoid arthritis, bowel disease which consequently lead to tissue destruction, inflammation and dysfunctioning of body organs...

IK can downregulate interferon (IFN)-γ-induced major histocompatibility complex (MHC) class II expression through the MHC class II transactivator, which suggests that IK can inhibit the interactions between immune cells. We delivered adeno-associated virus serotype 2 (AAV2) encoding the genes for truncated IK (tIK) or green fluorescent protein (GFP) to DBA1/J mice via intravenous injection. Seven weeks after injection, collagen-induced arthritis (CIA) was induced in the AAV2 treated mice. AAV2-tIK injection reduced the severity of arthritis and the percentage of pathogenic Th17 cells compared with AAV2-GFP injection...

Genes involved in regulation of the nuclear factor-κB (NF-κB)-pathway are suggested to play a role in pathogenesis of rheumatoid arthritis (RA). In the present study, genetic polymorphisms of TLR2, TLR4, TLR9 and NF-κB1 genes were investigated to assess their associations with RA susceptibility, progression and response to anti-TNF-α therapy. A group of 110 RA patients and 126 healthy individuals were genotyped for TLR2 (rs111200466), TLR4 (rs4986790, rs4986791), TLR9 (rs5743836, rs187084) and NF-κB1 (rs28362491) alleles...

Angiogenesis is involved in maintaining normal physiological processes like embryonic development, wound healing, inflammation and reproduction. Pathogenesis of various diseases like diabetic retinopathy, rheumatoid arthritis and cancer are associated with imbalanced angiogenesis. Angiogenic stimulators and inhibitors act together for keeping angiogenic switch in balance. Recently miRNAs have been found to regulate various stages of angiogenesis. miRNAs are 21-23 nucleotides long, single stranded, noncoding RNA molecules generated endogenously...

BACKGROUND: Rheumatoid arthritis is a symmetric inflammatory polyarthritis associated with high concentrations of pro-inflammatory cytokines including TNF-α. Adalimumab is a monoclonal antibody (mAb) that binds TNF-α, and is widely used to treat rheumatoid arthritis. Despite its proven clinical efficacy, adalimumab and other therapeutic mAbs have disadvantages including the requirement for repeated bolus injections and the appearance of treatment limiting anti-drug antibodies. To address these issues, we have developed an innovative ex-vivo gene therapy approach, Transduced Autologous Restorative Gene Therapy (TARGT), to produce and secrete adalimumab for the treatment of RA...

Inflammation is associated with glenohumeral arthritis and rotator cuff tendon tears. Epigenetically, miRNAs tightly regulate various genes involved in the inflammatory response. Alterations in the expression profile of miRNAs and the elucidation of their target genes with respect to the pathophysiology could improve the understanding of their regulatory role and therapeutic potential. Here, we screened key miRNAs that mediate inflammation and linked with JAK2/STAT3 pathway with respect to the coincidence of glenohumeral arthritis in patients suffering from rotator cuff injury (RCI)...

OBJECTIVES: Hyperzincaemia/hypercalprotectinemia (Hz/Hc) syndrome is a recently described condition caused by a specific de novo mutation (E250K) affecting PSTPIP1 gene. It has a phenotype distinct from classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome that includes severe systemic and cutaneous inflammation, hepatosplenomegaly, arthritis without sequelae, pancytopenia and failure to thrive. METHODS: We describe an 8-year-old boy who presented recurrent right knee swelling mimicking septic arthritis and persistent bone marrow involvement, without cutaneous involvement...

Familial Mediterranean fever (FMF) is the most common monogenic periodic fever syndrome and characterized by recurrent episodes of fever, serositis, arthritis, dermal manifestations, and long-term renal complications. The MEFV gene was described in 1997 as the gene responsible for FMF and is inherited in autosomal recessive manner. It encodes mutated protein pyrin, an important player in the innate immune system and the component of inflammasome which leads to exaggerated inflammatory response through uncontrolled production of interleukin-1...