Multiple Therapeutic Applications of RBM-007, an Anti-FGF2 Aptamer.

Yoshikazu Nakamura

doi:10.3390/cells10071617

Abstract

Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis, but is not the only player with an angiogenic function. Fibroblast growth factor-2 (FGF2), which was discovered before VEGF, is also an angiogenic growth factor. It has been shown that FGF2 plays positive pathophysiological roles in tissue remodeling, bone health, and regeneration, such as the repair of neuronal damage, skin wound healing, joint protection, and the control of hypertension. Targeting FGF2 as a therapeutic tool in disease treatment through clinically useful inhibitors has not been developed until recently. An isolated inhibitory RNA aptamer against FGF2, named RBM-007, has followed an extensive preclinical study, with two clinical trials in phase 2 and phase 1, respectively, underway to assess the therapeutic impact in age-related macular degeneration (wet AMD) and achondroplasia (ACH), respectively. Moreover, showing broad therapeutic potential, preclinical evidence supports the use of RBM-007 in the treatment of lung cancer and cancer pain.

Highlights

In mammals, fibroblast growth factors (FGF) have 22 known members that exert important functions in regulating cell proliferation, differentiation, and migration [1,2]
Findings show that Fibroblast growth factor-2 (FGF2) is secreted from Cancer-associated fibroblasts (CAFs) and contributes to tumor cell growth by stimulating synthesis of more collagen and the secretion of inflammatory cell-recruiting cytokines via CAFs expressed TGFβ, MMP7, and FGF9 [62]
Compared to co-cultures with wild-type fibroblasts, co-culture with Fgf2−/− fibroblasts resulted in fewer and smaller colonies [62]. These findings indicate that the expression of FGF2 in CAFs contributes to tumor cell growth

Summary

Introduction

Fibroblast growth factors (FGF) have 22 known members that exert important functions in regulating cell proliferation, differentiation, and migration [1,2]. FGF2 generally plays a positive role in bone health; several in vitro studies have demonstrated the adverse role of FGF2 in the progression of bone disease [4,5,6,7]. Recent advances in understanding the role of FGF2 in bone formation alternatively posit that the pharmaceutical manipulation of FGF2 signaling may be a promising approach for bone disease therapy. Focusing on the therapeutic potential in inhibiting FGF2, we developed the inhibitory RNA aptamer, RBM-007 [13]. Aptamers are single-stranded short oligonucleotides selected in vitro from a large random sequence library, and are applicable to therapies because of several pharmaceutical advantages, such as a medium size between small molecules and antibodies, chemical synthesis, production cost, and low antigenicity [14]. Our studies highlight the broad therapeutic potential of RBM-007 and the multifunctionality of FGF2 (Figure 1) in the treatments of wet AMD, achondroplasia, cancer pain and lung cancer, respectively, while providing perspectives on these therapeutic applicabilities

Anti-FGF2 Aptamer

Therapeutic Application in Age-Related Macular Degeneration

Therapeutic Application in Achondroplasia

Therapeutic Application in Cancer Pain

Conclusion and Perspectives