Animal models provide insight into exudative AMD

November 15, 2004

Animal models are useful tools for research into the etiology, progression, and treatment of disease. Several animal models have been developed to mimic various features of ophthalmic angiogenesis and many of these models have been used to assess the efficacy and safety of treatment regimens prior to clinical use, as well as to test formulations of drugs and modes of administration.

Animal models are useful tools for research into the etiology, progression, and treatment of disease. Several animal models have been developed to mimic various features of ophthalmic angiogenesis and many of these models have been used to assess the efficacy and safety of treatment regimens prior to clinical use, as well as to test formulations of drugs and modes of administration.

A close look at preclinical models is warranted given the large volume of clinical data that is becoming available on new treatments for choroidal neo-vascularization (CNV). Clinicians already have, and will be getting more, clinical data on pegaptanib sodium (Macugen, Eyetech Pharmaceuticals), anecortave acetate (Retaane, Alcon Laboratories Inc.), and ranibizumab (Lucentis, Genentech) as well as others.

This article will review several distinct models of ocular neovascularization and the advantages and disadvantages of each as they relate to drug development. As more and more therapeutic molecules are developed, understanding of clinical applications of animal models will be ever more important in understanding how preclinical efficacy of a new drug will predict efficacy in humans.

When evaluating different classes of drugs, success in a single model is rarely indicative of a highly therapeutic molecule.

However, success in several models, across multiple species and mechanisms of induced disease increases the likelihood of achieving a unique molecule with far-reaching therapeutic implications.

One example of this is anecortave acetate, which was evaluated in nine preclinical models before moving on to clinical evaluation.1

The preclinical development of anecortave acetate included everything from assessing effects on endothelial cell migration and proliferation, to effects on angiogenesis using isolated tissue preparations such as the chick chorioallantoic membrane (CAM) assay, to effects on angiogenesis in various in vivo models such as the lipopolysaccharide (LPS)-induced corneal pocket model, oxygen-induced retinopathy model, and laser-induced CNV model.2

In the next 12 to 24 months release of more pre-clinical data on pegaptanib sodium, anecortave acetate, and ranibizumab is anticipated, which will allow a closer comparison of the three drugs.

vitro models: tools for screening Endothelial cell migration and proliferation. In the initial stages of development, molecules with therapeutic potential are often screened using in vitro endothelial cell proliferation and migration models. These models evaluate the proliferation, migration, and tube formation of cultured endothelial cells as indicators of angiostatic potential on a cellular basis.3 These models are limited because the endothelial cells are removed from the overall system, but it is often used as an early stage screening tool.

A variation on these models has been through the use of a matrigel system.

This model uses endothelial cells labeled with fluorescein to monitor migration and division of the cells through a matrigel matrix. The matrix itself is impregnated with multiple pro-growth factors and a coating only allows penetration of invasive cells, which can be identified by the label.