A report from a per-protocol interim analysis of an ongoing phase 2
study suggests that antisense oligonucleotide eye drops may inhibit corneal
The eye drops, called GS-101, consist of antisense oligonucleotides
designed to inhibit the insulin receptor substrate-1 (IRS-1) site, which is an
important zone in protein synthesis for formation and growth of new blood
vessels. The drops have some anti-VEGF capabilities but do not completely shut
off VEGF activity at the cornea, which may be important for epithelial and
stromal wound healing and corneal nerve repair.
According to Claus Cursiefen, MD, lead author on the study, the drops
target a broader range of factors that lead to corneal angiogenesis and may not
have the potentially deleterious effects of completely shutting off VEGF
function at the cornea.
Neutralizing VEGF at the cornea may have several side effects,
such as neurotrophic keratopathy and wound healing issues. Therefore, it may be
wise to not only focus on VEGF and not completely inhibit it, Dr.
In murine models, mice deficient in IRS-1 produced less retinal
neovascularization in response to neonatal hypoxia. Preclinical studies have
shown that the drops also reduce inflammatory cytokine release, meaning it may
be an ideal option for patients with refractory progressive neovascularization.
Host corneal neovascularization is a significant risk factor for corneal
graft rejection before and after transplantation. However, to date, no
therapeutic options exist for anterior segment neovascularization, and only
suggestive animal studies and off-label use of Avastin (bevacizumab, Genentech)
in humans have been reported.
Early case reports on topical use of bevacizumab have suggested the
possibility of epithelial defect, epithelial erosion and corneal thinning
associated with its use. The use of bevacizumab as a topical application or as
a subconjunctival injection is being studied in a number of trials listed on
So far, the phase 2 study of GS-101 has noted three cases of ocular
surface discomfort associated with the drops and no serious side effects. One
patient discontinued use of the study drug because of complaints of a painful
eye and a pressure sensation.
It is still too early to determine if GS-101 offers a safety advantage,
according to Dr. Cursiefen. Theoretically, though, there may be a benefit in
the topical approach to treating corneal angiogenesis.
It would be hard to justify systemic side effects with a systemic
treatment when treating such an amenable tissue as the cornea, Dr.
Cursiefen said. In addition, by topical treatment, tissue levels can be
reached, which can hardly be achieved using systemic treatment.
In the study, 40 patients were treated with two drops per day for 3
months with one of three dosing strengths or placebo. Corneal
neovascularization was linked to a number of underlying causes, notably alkali
burns in nine patients (22.5%), contact lens misuse in seven patients (17.5%),
herpes simplex keratitis in seven patients (17.5%) and graft rejection in five
In patients in the low-dose group (43 µg/day total), corneal
neovascularization appeared to stabilize, progressing to cover an additional
0.07% of the cornea over the duration of the study compared with 0.89% in
placebo. In the intermediate-dose group (86 µg/day total), corneal
neovascularization regressed 2.04% of the corneal surface.
There appeared to be no benefit in the high-dose group (172 µg/day
total), as corneal neovascularization progressed by 1.60%. However, there were
two outliers in the high-dose group representing patients who did not respond
to therapy. When those two patients were removed from the analysis, the rate of
regression was similar to results in the 86-µg/day group. by
- Cursiefen C, Bock F, Horn FK, et al. GS-101 antisense
oligonucleotide eye drops inhibit corneal neovascularization: interim results
of a randomized phase II trial. Ophthalmology.
- Claus Cursiefen, MD, can be reached at the Department of
Ophthalmology, Friedrich-Alexander University Erlangen-Nürnberg,
Schwabachanlage 6, 91054 Erlangen, Germany; e-mail: