Growth Factors

Growth factors are a diverse group of proteins that act at autocrine and paracrine levels to affect various cellular processes, including metabolic regulation, tissue differentiation, cell growth and proliferation, maintenance of viability, and changes in cell morphology. Growth factors are synthesized in a variety of cells and have a spectrum of target cells and tissues. The following growth factors have been found in retina, vitreous humor, aqueous humor, and corneal tissues:

• epidermal growth factor

• fibroblast growth factors

• transforming growth factor βs

• vascular endothelial growth factor (VEGF)

• insulin-like growth factors

These growth factors are capable of diverse, synergistic, and sometimes antagonistic biological activities.

Under normal physiologic conditions, the complex and delicate coordination of both the effects of and the interactions among growth factors maintains the homeostasis of intraocular tissues. The net effect of a growth factor depends on its bioavailability, which is determined by its concentration; its binding to carrier proteins; the level of its receptor in the target tissue; and the presence of complementary or antagonistic regulatory factors.

Pathologically, the breakdown of the blood–ocular barrier disrupts the balance among growth factors in the ocular media and tissues and may result in various abnormalities. Disruption in the balance among isoforms of transforming growth factor βs, basic fibroblast growth factor, VEGF, and insulin-like growth factors is thought to cause ocular neovascularization. Transforming growth factor βs and platelet-derived growth factor are also implicated in the pathogenesis of proliferative vitreoretinopathy and in the excessive proliferation of Tenon capsule fibroblasts, which can result in scarring of the glaucoma filtration bleb. Increased concentrations of insulin-like growth factors in plasmoid aqueous humor may be responsible for the abnormal hyperplastic response of the lens epithelium and corneal endothelium observed in inflammatory conditions and in ocular trauma.

Identifying growth factors and understanding their mechanisms of action in the eye can provide the ophthalmologist with new methods for manipulation of and intervention in ocular disorders. Epidermal and fibroblast growth factors can accelerate corneal wound repair after surgery, chemical burns, or ulcers and can increase the number of corneal endothelial cells. Fibroblast growth factor also was shown to delay the process of retinal dystrophy in Royal College of Surgeons rats.

VEGF, also known as vasculotropin, deserves special mention. It is a dimeric, heparinbinding, polypeptide mitogen with 4 isoforms that are generated from alternative splicing of mRNA. The VEGF gene is widely expressed in actively proliferating vascular tissue and is implicated in the pathogenesis of various retinovascular conditions.

Intravitreal injections of VEGF inhibitors are used to treat neovascular (“wet”) AMD. Patients with choroidal neovascularization who were treated with anti-VEGF showed a slower loss of vision than occurred in controls, especially moderate (>3 lines of vision lost) to severe (>6 lines lost) vision loss, and in many cases, an improvement in vision (≥3 lines of visual acuity). Pegaptanib, the first approved drug for choroidal neovascularization, requires intravitreal injections every 6 weeks for up to 2 years. Newer drugs have largely supplanted pegaptanib.

Bevacizumab, a full-length antibody against VEGF approved for the intravenous treatment of advanced carcinomas, has been used extensively in ophthalmology for neovascular AMD, diabetic retinopathy, retinal vein occlusions, retinopathy of prematurity, and other chorioretinal vascular disorders. Ranibizumab is a monoclonal antibody fragment (Fab) derived from the same parent mouse antibody as bevacizumab and demonstrates similar efficacy. Pegaptanib and ranibizumab were developed for intraocular use, for which they are approved by the FDA, whereas the use of bevacizumab remains off-label. Although these drugs exhibit excellent safety profiles, ocular and systemic complications, particularly thromboembolic events, remain a concern for patients receiving therapy.

Aflibercept is a novel recombinant fusion protein engineered to bind all isoforms of VEGF A, VEGF B, and placental growth factor. It has been approved for the treatment of neovascular AMD, retinal vein occlusions, and diabetic macular edema. It may have a longer duration of action than other anti-VEGF therapies; a monthly loading dose is administered for 3 months, after which the drug can be given every 2 months depending on the condition (see BCSC Section 12, Retina and Vitreous).

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.