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Development and Evaluation of Therapeutics for Resolution of Pathological
Vascularization-Associated Diseases. Timothy P. Foster*1, Charles Nichols2 and Daniel
Kapusta2. Departments of Microbiology, Immunology and Parasitology1 and Pharmacology2,
Louisiana State University Health Sciences Center, New Orleans, LA.
Background and Objective: Physiological angiogenesis and neovascularization are required
for embryonic development, tissue remodeling and wound healing. However, in certain tissues
and diseases, dysregulation of these tightly controlled processes can result in vascularizationmediated pathological conditions. In ocular and dermal diseases, as well as cancers,
vascularization of normally avascular tissue feeds a cascade of host-mediated responses that
exacerbates the pathological processes and worsens the prognosis of disease resolution.
Methods: We have developed several pharmaceutical preparations that target and disrupt
pathways associated with disease promoting vascularization processes. The effects of these
drug preparations were assessed on primary human vascular endothelial cells by whole
genome computational approaches, as well as through in vitro, ex vivo and in vivo angiogenesis
and disease models.
Results: Two target compounds were identified that exhibited strong anti-neovascularization
and anti-angiogenic properties. Computational characterization of global effects on vascular
endothelium indicated that these compounds would prevent angiogenesis by inhibiting multiple
pathways/processes. These predictions were confirmed through in vitro and ex vivo
angiogenesis assays. In two ocular disease models, treatment with these compounds exhibited
strong inhibition of pathological vascularization processes and prevented subsequent disease
development.
Conclusions: Unlike current single process targeted angiopreventatives, which limits their
therapeutic applications, our lead compounds suppressed multiple processes associated with
pathological vascularization enabling broader range of treatment for vascularizaiton-associated
diseases.
This research was supported by P30GM106392.