TY - JOUR
T1 - Effects of TAK-639, a novel topical C-type natriuretic peptide analog, on intraocular pressure and aqueous humor dynamics in mice
AU - Millar, J. Cameron
AU - Savinainen, Anneli
AU - Josiah, Serene
AU - Pang, Iok Hou
N1 - Funding Information:
The in vivo portion of this study was funded by Shire , a Takeda company. In vitro assays were funded by Alcon Research Ltd. The data subsequently became an asset of Shire. Under direction of the authors, Malcolm Darkes, PhD, and Shirley Louise-May, PhD, of Excel Scientific Solutions provided writing assistance, which was funded by Takeda. The interpretation of the data was made by the authors independently.
Funding Information:
The in vivo portion of this study was funded by Shire, a Takeda company. In vitro assays were funded by Alcon Research Ltd. The data subsequently became an asset of Shire. Under direction of the authors, Malcolm Darkes, PhD, and Shirley Louise-May, PhD, of Excel Scientific Solutions provided writing assistance, which was funded by Takeda. The interpretation of the data was made by the authors independently.Iok-Hou Pang and J. Cameron Millar received research support from Shire Human Genetic Therapies, Inc. Anneli Savinainen was an employee of Shire, now a part of Takeda, at the time of this study. Serene Josiah is an employee of Shire, now a part of Takeda.
Publisher Copyright:
© 2019
PY - 2019/11
Y1 - 2019/11
N2 - Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness, and individuals with ocular hypertension are at risk to develop POAG. Currently, the only modifiable risk factor for glaucoma progression is lowering of intraocular pressure (IOP). A novel mechanism for lowering IOP involves activation of the type B natriuretic peptide receptor (NPR-B), the naturally occurring agonist of which is C-type natriuretic peptide (CNP). Being a cyclic peptide of 22 amino acids, CNP does not readily penetrate the cornea and its ocular hypotensive effect requires intraocular injection. TAK-639 is a synthetic, cornea-permeable, 9-amino acid CNP analog has been studied for the treatment of ocular hypertension and POAG. We assessed TAK-639 in a receptor binding profile and the effects of TAK-639 on NPR-B-mediated cyclic GMP production in cultured transformed human trabecular meshwork (TM) cells (GTM-3). We also evaluated the effects of topical ocular administration of TAK-639 on mouse IOP and aqueous humor dynamics. Among 89 non-natriuretic peptide receptors, transporters, and channels evaluated, TAK-639 at 10 μM displaced ligand binding by more than 50% to only two receptors: the type 2 angiotensin receptor (IC50 = 8.2 μM) and the cholecystokinin A receptor (IC50 = 25.8 μM). In vitro, TAK-639 selectively activates NPR-B (EC50 = 61 ± 11 nM; GTM-3 cells) relative to NPR-A (EC50 = 2179 ± 670 nM; 293T cells). In vivo, TAK-639 lowered mouse IOP by three mechanisms: increase in aqueous humor outflow facility (C), reduction in the aqueous humor formation rate (Fin), and reduction in episcleral venous pressure (Pe). The maximum mean IOP decreases from baseline were −12.1%, −21.0%, and −36.1% for 0.1%, 0.3%, and 0.6% doses of TAK-639, respectively. Maximum IOP-lowering effect was seen at 2 h, and the duration of action was >6 h. With TAK-639 0.6%, at 2 h post-dose, aqueous outflow facility (C) increased by 155.8%, Fin decreased by 41.0%, the uveoscleral outflow rate (Fu) decreased by 52.6%, and Pe decreased by 31.5% (all p < 0.05). No ocular adverse effects were observed. TAK-639 is an efficacious IOP-lowering agent, with a unique combination of mechanisms of action on both aqueous formation and aqueous outflow facility. Further study of this mechanism of treatment may optimize pharmacologic outcomes and provide disease management in patients with POAG and ocular hypertension.
AB - Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness, and individuals with ocular hypertension are at risk to develop POAG. Currently, the only modifiable risk factor for glaucoma progression is lowering of intraocular pressure (IOP). A novel mechanism for lowering IOP involves activation of the type B natriuretic peptide receptor (NPR-B), the naturally occurring agonist of which is C-type natriuretic peptide (CNP). Being a cyclic peptide of 22 amino acids, CNP does not readily penetrate the cornea and its ocular hypotensive effect requires intraocular injection. TAK-639 is a synthetic, cornea-permeable, 9-amino acid CNP analog has been studied for the treatment of ocular hypertension and POAG. We assessed TAK-639 in a receptor binding profile and the effects of TAK-639 on NPR-B-mediated cyclic GMP production in cultured transformed human trabecular meshwork (TM) cells (GTM-3). We also evaluated the effects of topical ocular administration of TAK-639 on mouse IOP and aqueous humor dynamics. Among 89 non-natriuretic peptide receptors, transporters, and channels evaluated, TAK-639 at 10 μM displaced ligand binding by more than 50% to only two receptors: the type 2 angiotensin receptor (IC50 = 8.2 μM) and the cholecystokinin A receptor (IC50 = 25.8 μM). In vitro, TAK-639 selectively activates NPR-B (EC50 = 61 ± 11 nM; GTM-3 cells) relative to NPR-A (EC50 = 2179 ± 670 nM; 293T cells). In vivo, TAK-639 lowered mouse IOP by three mechanisms: increase in aqueous humor outflow facility (C), reduction in the aqueous humor formation rate (Fin), and reduction in episcleral venous pressure (Pe). The maximum mean IOP decreases from baseline were −12.1%, −21.0%, and −36.1% for 0.1%, 0.3%, and 0.6% doses of TAK-639, respectively. Maximum IOP-lowering effect was seen at 2 h, and the duration of action was >6 h. With TAK-639 0.6%, at 2 h post-dose, aqueous outflow facility (C) increased by 155.8%, Fin decreased by 41.0%, the uveoscleral outflow rate (Fu) decreased by 52.6%, and Pe decreased by 31.5% (all p < 0.05). No ocular adverse effects were observed. TAK-639 is an efficacious IOP-lowering agent, with a unique combination of mechanisms of action on both aqueous formation and aqueous outflow facility. Further study of this mechanism of treatment may optimize pharmacologic outcomes and provide disease management in patients with POAG and ocular hypertension.
KW - Aqueous humor
KW - C-type natriuretic peptide
KW - Intraocular pressure
KW - Open-angle glaucoma
KW - Trabecular meshwork
UR - http://www.scopus.com/inward/record.url?scp=85071544285&partnerID=8YFLogxK
U2 - 10.1016/j.exer.2019.107763
DO - 10.1016/j.exer.2019.107763
M3 - Article
C2 - 31421135
AN - SCOPUS:85071544285
SN - 0014-4835
VL - 188
JO - Experimental Eye Research
JF - Experimental Eye Research
M1 - 107763
ER -