VEGFR-1 as a target for rheumatoid arthritis therapies

Rheumatoid arthritis (RA) is one of the more common autoimmune diseases along with multiple sclerosis (MS), 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. An estimated 5 million individuals suffer from RA, 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 RA.

One field of research extensively analyzed in “Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates” is angiogenesis. The joint in RA contains a proliferating synovium, which forms an invading tissue termed the pannus. Persistent angiogenesis is critical to maintaining the chronic architectural changes in the RA synovium via delivery of nutrients and inflammatory cells. Although the importance of angiogenesis in arthritis progression has been well recognized, the molecular mechanisms promoting angiogenesis in RA have not been clearly identified. In our previous edition of TherapeuticAdvances we highlight the central role of Tie2 in this process (click here). Here we describe a key study supporting VEGFR-1 as a target.

Discovered in the 1980's, VEGF is one of the archetypal angiogenic growth factors. VEGF specifically acts on endothelial cells binding to endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1) and KDR/flk-1 (VEGFR-2). In addition to VEGF, placental growth factor also binds to VEGFR-1. VEGFR-2 is exclusively expressed in endothelial cells and appears to play a pivotal role in endothelial cell differentiation and vasculogenesis. A third receptor, VEGFR-3 has been implicated in lymphogenesis. VEGF is distributed in the perivascular space expressed by subsynovial macrophages and synovial lining cells in the synovial tissues of RA patients. VEGF is elevated in RA patients and has been implicated in RA-associated endothelial cell migration, proliferation and chemotaxis. In addition, endothelial fenestration, a characteristic of synovial vessels, is induced by VEGF. In an animal model of RA, treatment with anti-VEGFR-1 or soluble VEGFR-1 strongly attenuated the disease; treatment with anti-VEGFR-2 had no effect on disease progress. Hence the development of VEGFR-1 antagonists may represent an approach to the treatment of RA. Of interest this differs from angiogenesis inhibitors that are in development for the treatment of cancer and which block both VEGR-1 and VEGFR-2 (see also the Focus on Angiogenesis section of this edition of TherapeuticAdvances with suggests that VEGFR-2 receptors are also targets for angiogenesis in the context of obesity).

In a recent Gene Therapy paper, Afuwape, Feldmann & Paleolog describe the therapeutic efficacy of viral delivery of soluble VEGFR-1. The authors treated mice with collagen-induced arthritis, at the time of disease onset, with an adenovirus expressing VEGFR-1. Intravenous administration suppressed the development of disease even though over-expression of VEGFR-1 was transient. This corresponded to a remarkable absence of severe bone and cartilage erosion and also joint hypervascularization. Of interest the pathophysiological role of VEGFR-1 in the development of RA seems to involve VEGF rather the other ligand of this receptor, PlGF which could not be detected in arthritic joints.

The development of biologic therapies such as antibodies and soluble receptors has gained considerable attention in the context of RA treatments. This study confirms the therapeutic potential of agents that block VEGFR-1 and in the particular the use of soluble VEGFR-1 receptors. Furthermore the use of viral vectors to deliver soluble VEGFR-1 is supported by the present study even though transient expression and the development of anti-adenoviral antibodies limited efficacy. Further development allowing optimized viral delivery should enhance the benefits of this approach still further and the use of such technology for this application is awaited.

Entry date Monday, November 17, 2003

Adapted from Afuwape et al, Gene Ther. 2003 Nov;10(23):1950-60