TY - JOUR
T1 - Successful proof-of-concept for topical delivery of novel peptide ALM201 with potential utility for treating neovascular eye disorders
AU - Obasanmi, Gideon
AU - Nesbit, M. Andrew
AU - Cobice, Diego
AU - Mackay, Logan
AU - McGimpsey, Stuart
AU - Wappett, Mark
AU - Cranston, Aaron N.
AU - Moore, CB Tara
PY - 2022/4/4
Y1 - 2022/4/4
N2 - Objective
To evaluate the therapeutic benefit of a novel peptide, ALM201, in ocular pathological vascularization.
Design
Experimental study in mouse, rat and rabbit animal models
Methods
Corneal vascularization was scored for vessel density and vessel distance to suture in a rat corneal suture model. Ocular penetration and biodistribution were evaluated by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) one-hour after topical ALM201 eye drop application to rabbit eyes. An ex vivo mouse choroidal sprouting assay (CSA), with aflibercept as positive control, was used to evaluate choroidal NV (chNV) in the posterior segment tissue. Efficacy of topical ALM201 was assessed in vivo using a rat laser chNV model of neovascular age-related macular degeneration (nAMD), with intravitreal aflibercept as a comparator molecule.
Main Outcome Measures
Clinical scoring and histology of vascularized corneas, sprouting area, lesion size and vessel leakiness in posterior segments.
Results
Assessment of ALM201 treatment in the rat corneal suture model showed a significant decrease in vessel density (p = 0.0065) and vessel distance to suture (p = 0.021) compared to vehicle control (PBS). Infiltration of inflammatory cells into the corneal stroma was also significantly reduced compared to PBS (724.5 ± 122 cells vs. 1837 ± 195.9 cells/mm2, respectively; p = 0.0029). Biodistribution in rabbit eyes confirmed ALM201 bioavailability in both anterior and posterior ocular segments one-hour post-topical instillation. ALM201 treatment significantly suppressed choroid vessel sprouting when compared to PBS treatment (44.5 ± 14.31 vs. 120.9 ± 33.37 pixels, respectively; p = 0.04), and was not inferior to aflibercept (65.63 ± 11.86 pixels, p = 0.7459). Furthermore, topical ALM201 was shown to significantly improve vessel leakiness (2.1 ± 0.7 vs. 2.9 ± 0.1 HRA, p = 0.0274) and lesion size (144,729 ± 33,239 vs. 187,923 ± 28,575 μm3, p = 0.03) in the rat laser chNV model of nAMD when compared to topical PBS vehicle.
Conclusions
ALM201 is a promising novel molecule with anti-inflammatory and anti-vascularization activity and is a strong candidate to meet the clinical need of a new, topically delivered, therapeutic agent for treating inflammation and pathological vascularization in the anterior and posterior segments of the eye.
AB - Objective
To evaluate the therapeutic benefit of a novel peptide, ALM201, in ocular pathological vascularization.
Design
Experimental study in mouse, rat and rabbit animal models
Methods
Corneal vascularization was scored for vessel density and vessel distance to suture in a rat corneal suture model. Ocular penetration and biodistribution were evaluated by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) one-hour after topical ALM201 eye drop application to rabbit eyes. An ex vivo mouse choroidal sprouting assay (CSA), with aflibercept as positive control, was used to evaluate choroidal NV (chNV) in the posterior segment tissue. Efficacy of topical ALM201 was assessed in vivo using a rat laser chNV model of neovascular age-related macular degeneration (nAMD), with intravitreal aflibercept as a comparator molecule.
Main Outcome Measures
Clinical scoring and histology of vascularized corneas, sprouting area, lesion size and vessel leakiness in posterior segments.
Results
Assessment of ALM201 treatment in the rat corneal suture model showed a significant decrease in vessel density (p = 0.0065) and vessel distance to suture (p = 0.021) compared to vehicle control (PBS). Infiltration of inflammatory cells into the corneal stroma was also significantly reduced compared to PBS (724.5 ± 122 cells vs. 1837 ± 195.9 cells/mm2, respectively; p = 0.0029). Biodistribution in rabbit eyes confirmed ALM201 bioavailability in both anterior and posterior ocular segments one-hour post-topical instillation. ALM201 treatment significantly suppressed choroid vessel sprouting when compared to PBS treatment (44.5 ± 14.31 vs. 120.9 ± 33.37 pixels, respectively; p = 0.04), and was not inferior to aflibercept (65.63 ± 11.86 pixels, p = 0.7459). Furthermore, topical ALM201 was shown to significantly improve vessel leakiness (2.1 ± 0.7 vs. 2.9 ± 0.1 HRA, p = 0.0274) and lesion size (144,729 ± 33,239 vs. 187,923 ± 28,575 μm3, p = 0.03) in the rat laser chNV model of nAMD when compared to topical PBS vehicle.
Conclusions
ALM201 is a promising novel molecule with anti-inflammatory and anti-vascularization activity and is a strong candidate to meet the clinical need of a new, topically delivered, therapeutic agent for treating inflammation and pathological vascularization in the anterior and posterior segments of the eye.
U2 - 10.1016/j.xops.2022.100150
DO - 10.1016/j.xops.2022.100150
M3 - Article
C2 - 36249680
JO - Ophthalmology Science
JF - Ophthalmology Science
SN - 2666-9145
M1 - 100150
ER -