PEDF: A Multifunctional Protein

Gerald J. Chader

A novel differentiative activity was first described in a conditioned medium of cultured human retinal pigment epithelial (RPE) cells that promoted a more neuronal phenotype in cultured retinoblastoma cells. This factor has now been isolated and the gene cloned. The gene product, PEDF, is a 50 kD protein, of the serpin supergene family, which has been found to be synthesized in many cells types, to exhibit a number of activities, and to be involved in a wide range of important cellular activities. Its expression, for example, is cell cycle-specific, and it appears to be intimately involved in cellular aging and senescence. Functionally, PEDF can act as an excellent neuron-survival, antiapoptotic agent under a variety of in vitro and in vivo conditions in retina and brain. Thus, its use in neurodegenerative diseases is apparent. It also inhibits glial growth in mixed neuron/glia brain cultures without affecting preformed glial elements-as such a “gliastatic” agent with possible clinical use in glosis. Finally, PEDF has potent antineovascular and antitumor activity, its loss being permissive to ischemia-driven pathology. It is an inhibitor of angiogenesis that is involved not only in protection against inappropriate vessel growth in the adult but also seemingly in normal embryonic development as well-where avascularity is important as in cornea, vitreous, and within the interphotoreceptor matrix. Thus, PEDF appears to play multiple and diverse roles in development, homeostasis, aging, and pathophysiologylogy. Human diseases such as cancer and diabetes, as well as neurodegenerative diseases of the central nervous system and the peripheral nervous system, may benefit from treatment with PEDF. In the eye, PEDF could be used to great advantage in controlling neovascularization in the two major blinding diseases of age-related macular degeneration and diabetic retinopathy as well as a neuron-survival agent in retinitis pigmentosa and glaucoma as well.