HDAC inhibitors for the treatment of rheumatoid arthritis

Rheumatoid arthritis is one of the more common autoimmune diseases along with multiple sclerosis, type I diabetes and Crohn’s disease. Approximately one in five people in the western world suffer from autoimmune diseases and some estimates indicate that 75% of these are women. In total it is predicted that the annual value of the market for drugs used to treat autoimmune disease will soon exceed $20 billion. An estimated 5 million individuals suffer from rheumatoid arthritis, a figure which will increase to 5.7 million by 2010. As described in LeadDiscovery’s state of the art analysis of rheumatoid arthritis drug discovery targets and therapeutic candidates (click here), this field is attracting massive interest in the wake of resurgent R&D activity which has advanced our understanding of the etiology of rheumatoid arthritis.

Rheumatoid arthritis is a chronic syndrome characterized by non-specific, usually symmetrical inflammation of the peripheral joints, manifested by the formation of hypertrophied synovia known as panni. Pannus formation mirrors the destruction of articular and peri-articular structures, with or without generalized manifestations. The condition differs from osteoarthritis not only through the obligatory involvement of the immune system but also because disease onset occurs early on in life, generally between the ages of 20 and 50, although it can begin at any age. The inflammation involves the activation of T cells that subsequently infiltrate the synovium. Prolonged inflammation leads to pannus formation and the release of auto-destructive mediators.

The field of histone deacetylation continues to receive considerable interest due to the ability of histone deacetylase (HDAC) inhibitors to modulate transcriptional activity. Molecules from this therapeutic class can induce cell cycle arrest, differentiation and apoptosis and therefore have the potential to occupy an indomitable position in the fast-moving cytostatic market. In response to the emergence of HDAC inhibitors as a major therapeutic class in the fight against cancer LeadDiscovery recently published one of the most comprehensive overview of the pharmaceutical potential of HDAC inhibitors (click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer").

There are many similarities between rheumatoid arthritis and cancer: the hyper-proliferative pannus; a dependency on angiogenesis and certain mediators that are produced in both conditions. HDAC inhibitors have therefore been linked to a possible approach to rheumatoid arthritis. We highlighted in a recent TherapeuticAdvances editorial (click here), for example, UCSF research demonstrating that the inhibition of HDAC7 expression causes increased T cell apoptosis in response to TCR activation.

More recently Chung et al report that when investigated ex vivo, two different HDAC inhibitors inhibited histone H3 and H4 acetylation in synovial fibroblasts. This led to reduced proliferation, an effect which was greater in fibroblasts derived from rats with experimental rheumatoid arthritis than controls. In further in vivo studies continuous topical administration of HDAC inhibitors was found to locally reduce paw swelling by up to 50%. This effect was longer lasting than when oral hydrocortisone was administered and was mirrored by histological improvement; the expression of cell cycle inhibitors such as p16 INK4 and p21 Cip1 and; the reduced expression of TNF alpha, a cytokine which is central to the inflammatory process in rheumatoid arthritis.

The current study employed first generation HDAC inhibitors, phenylbutyrate and trichostatin A. Over the past year chemists have made significant advances to the development of more selective and less toxic HDAC inhibitors and the evaluation of such therapeutic candidates in models of rheumatoid arthritis is eagerly awaited. Furthermore as described in a recent edition of TherapeuticAdvances, Aton pharma have recently published data from phase I studies of the HDAC inhibitor, SAHA. When administered iv SAHA is well tolerated and was shown to produce an accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion suggesting that treatment was sufficient to inhibit histone deacetylation. This biological response was mirrored by an objective tumor regression. According to Aton Pharma separate Phase I studies have shown oral doses of SAHA to be readily bioavailable, and result in prolonged (8-10 hours) inhibition of HDAC in the blood cells of patients. Consequently the oral formulation of SAHA has now entered into phase II to determine the activity of oral SAHA in several solid tumors and in hematological tumors. Extension of clinical studies to investigate the efficacy of SAHA in patients with rheumatoid arthritis may now therefore be warranted.

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Entry date Tuesday, January 27, 2004

Adapted from Chung et al, Mol Ther. 2003 Nov; 8(5): 707-17.