Pegaptanib is the first anti-angiogenic agent launched for the treatment of agerelated
macular degeneration (AMD). Wet, or neovascular, AMD is the leading
cause of vision loss in the elderly; vision loss is the consequence of choroidal neovascularization,
leading to leakage of blood or serum, retinal detachment, and
fibrovascular scarring. The underlying factor in the neovascularization is angiogenesis,
the proliferation of new blood vessels from pre-existing vasculature. Vascular
endothelial growth factor (VEGF) is one of the stimulators of this angiogenesis, and
pegaptanib’s mechanism of action involves the high-affinity binding (Kd=50 pM)
of extracellular VEGF, thereby, effectively sequestering the protein to ultimately
prevent VEGF receptor activation. Pegaptanib is also classified as an RNA aptamer;
and as such, it is the first aptamer to be approved for a therapeutic application.
Aptamers are RNA or DNA oligonucleotides that are selected for their high-affinity
binding to specific proteins. Pegaptanib was identified by the systematic evolution of
ligands by the exponential enrichment (SELEX) technique. Since most aptamers are
sensitive to nuclease degradation, both SELEX and post-SELEX modifications have
been performed to confer nuclease resistance. Specifically, the sugar moieties of the
ribonucleotides are modified at the 2′-positions with either a methoxy or a fluorine in
most cases. Once the optimal sequence has been identified, the aptamer can be
amplified (by reverse transcription, amplification using the polymerase chain reaction,
and transcription) or synthesized by standard solid-phase oligonucleotide
methods. Other frequently reported adverse events, occurring in approximately
10–40% of patients, were anterior chamber inflammation, blurred vision,
conjunctival hemorrhage, cataract, corneal edema, eye discharge, eye irritation, eye
pain, hypertension, increased intraocular pressure, ocular discomfort, punctate
keratitis, reduced visual acuity, visual disturbance, vitreous floaters, and vitreous
opacities. Since the mode of drug delivery carries a risk of infection, pegaptanib is
contraindicated in patients with ocular or periocular infections.
