**7. References**

Aliabadi, H. M., Brocks, D. R., & Lavasanifar, A. (2005). Polymeric micelles for the solubilization and delivery of cyclosporine A: pharmacokinetics and biodistribution. *Biomaterials,* 26, 35, pp. 7251-7259.

Given the nature of rheumatoid arthritis, gene therapy, whereby nucleic acids are introduced to a cell to either "turn off" select genes or upregulate therapeutic genes, is an attractive alternative treatment strategy (Jorgensen & Apparailly, 2010). This approach is limited, however, by the necessity for local administration and low transfection efficiency; therefore, for practical use, drug delivery systems for gene therapy will be required. Small interfering RNA (siRNA), in particular, may be used to knockdown the expression of proinflammatory proteins at the mRNA level. Cationic liposomes, referred to as lipoplexes, have been designed to facilitate systemic delivery of siRNA for rheumatoid arthritis treatment (Khoury et al., 2006, 2008). When administered intravenously to arthritic mice, anti-TNF-, anti-IL-1, anti IL-6, and anti IL-18 siRNA successfully reduced inflammation, bone and cartilage degradation, and secretion of a number of proinflammatory cytokines, including TNF-and IL-1 (Khoury et al., 2006, 2008). Similarly, intraperitoneal administration of anti-TNF- siRNA complexed with chitosan nanoparticles to arthritic mice resulted in a significant reduction in joint swelling, cartilage degradation, and inflammatory cell infiltration (Fernandes et al., 2008). Chitosan nanoparticles were also used to deliver the IL-1 receptor antagonist (IL-1Ra) gene to arthritic rats (Fernandes et al., 2008). Rats treated with the chitosan-gene delivery system showed reduced bone turnover, as well as decreased expression of IL-1and PGE2, relative to control rats. The efficacy of the chitosan-IL-1Ra nanoparticles was further improved by modification with folate for active targeting (Fernandes et al., 2008). An innovative strategy towards gene therapy was designed by encapsulating a nuclear factor kappa B (NF-B) decoy into stealth lipid-based nanoparticles that were surface modified with folate (Hattori et al., 2006). NF-B regulates proinflammatory gene expression and is, therefore, a critical component of rheumatoid arthritis pathogenesis (Brown et al., 2008; Simmonds & Foxwell, 2008). *In vitro,* the nanoparticles were shown to release the NF-B into the cytoplasm, as indicated by a reduction in NF-B translocation into the nucleus (Hattori et al., 2006), which presumably will result in a decreased expression of proinflammatory cytokines and growth factors.

Although the advent of biologics markedly increased the number of available treatment options, numerous rheumatoid arthritis patients still use, either alone or in combination, NSAIDs, GCs, and conventional DMARDs. All of these compounds are associated with severe negative side effects resultant from non-specific organ toxicity. In some cases, the side effects necessitate the cessation of a treatment option that may be effectively altering the course of the disease. The application of drug delivery strategies, as outlined herein, promises to improve patient outcome by reducing the likelihood of an adverse reaction to NSAIDs, GCs, and biologic and conventional DMARDs. These same strategies may be extended in the future to facilitate diagnostic imaging and gene therapy, thereby further increasing the possibility of successfully controlling the progression of the disease in all

Aliabadi, H. M., Brocks, D. R., & Lavasanifar, A. (2005). Polymeric micelles for the

biodistribution. *Biomaterials,* 26, 35, pp. 7251-7259.

solubilization and delivery of cyclosporine A: pharmacokinetics and

**5.4 Gene therapy** 

**6. Conclusion** 

**7. References** 

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**7** 

**Proteasome Targeted Therapies** 

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease that primarily affects the joints. Approximately 0.5% of the adult population worldwide suffer from RA. The functional disability that results from progressive joint destruction is associated with substantial cost, significant morbidity and premature mortality [Carmona et al, 2010]. Pain and inflammation are initial symptoms followed by various degree of bone and cartilage destruction. During the last few decades' tremendous improvements have been made in search of therapies against RA. Disease modifying anti-rheumatic drugs (DMARDs) and biological therapies such as antagonists against TNF-α or IL-1 have provided efficient treatments and changed the shape of this disorder. However, the side effects, availability, and their focused approach to reduce inflammation have limited their scope. Thus there is a need of therapies targeting inflammation as well as reducing inflammatory pain and joint

Cytokines are key players in pathogenesis of RA [Brennan & McInnes, 2008]. Synovial fluid from RA joints contains large quantities of cytokines secreted by macrophages, dendritic cells, neutrophils and synovial fibroblasts [Raza et al, 2005]. Cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-17 (IL-17) stimulate the production of destructive proteases. Synthesis of these pro-inflammatory mediators is regulated by the transcription factor NF-κB, controlled by the ubiquitin proteasome system (UPS) [Baldwin, 1996]. UPS is a multicatalytic system of protein degradation and present in all cell types including neurons and glia cells and regulates numerous cellular functions by

The degradation and processing of cellular proteins is critical for cell survival, growth, and cell division. Proteolysis via the proteasome pathway plays an important role in a variety of basic cellular processes. These processes are regulation of cell cycle and division, modulation of the immune and inflammatory responses, intracellular signaling, and

Cellular proteins are mainly degraded in two ways: lysosomal degradation and ubiquitinmediated degradation. Proteolysis in lysosomes is a non-specific process. In higher

**1. Introduction** 

destruction in RA.

selectively degrading cellular proteins.

**2. Ubiquitin proteasome system** 

development and differentiation [Goldberg, 2003].

**in Rheumatoid Arthritis** 

Aisha Siddiqah Ahmed

*Karolinska Institutet* 

*Sweden* 

