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Ming Yuan, Hua Yang, Gaurang Patel, Adrianna Latuszek, Ying Hu, William Poueymirou, Jingtai Cao, William Olson, Brian Zambrowicz, Carmelo Romano; Intravitreal injection of NPR1 antibody in humanized NPR1 mice lowers intraocular pressure. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3771. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Natriuretic peptides (NPs, including ANP, BNP and CNP) and their receptors (NPR1, NPR2 and NPR3) play important roles in cardiovascular, skeletal and other systems by activating transmembrane guanylyl cyclases and elevating intracellular cGMP levels. Administration of NPs in animals lowered intraocular pressure (IOP). The present study was undertaken to evaluate the effect on IOP after intravitreal injection (IVT) of human NPR1 antibody into humanized NPR1 mice.
Humanized NPR1 mouse (NPR1hu/hu) was generated with VelociGene technology (Regeneron). IVT injection of 40 mg human NPR1 antibody or control Ab was performed in humanized or WT NPR1 mice. IOP was measured daily for four days after injection. To examine the dose response, 40, 12.6, 4mg human NPR1 antibody or 40 mg control Ab was injected intravitreally, and IOP was monitored daily. To test the effect of long term delivery Ab, AAV2 vectors expressing human NPR1 antibody or eGFP were injected, IOP was followed up for 7 weeks.
IVT of 40 mg NPR1 antibody into NPR1hu/hu mice significantly reduced IOP from Day 1 to 3 compared to control antibody. Average IOP change was 5 mmHg. However, in WT mice there was no IOP lowering effect. Dose response study showed that of 40 or 12.6 mg IVT of NPR1 antibody had similar IOP lowering effect, while the effect of 40 mg NPR1 antibody lasted longer than 12.6 mg NPR1 antibody. IVT of 4 mg NPR1 antibody did not reduce IOP. No IOP effect was found after IVT AAV2-GFP or AAV2- NPR1 antibody at all experimental time points. This could be due to the low expression of NPR1 antibody i.e. only 10ng in the whole eye lysate was detected.
Our data demonstrated that IVT administration of human NPR1 antibody in humanized NPR1 mice could reduce IOP significantly. NPR1 could be a promising therapeutic target for lowering IOP in glaucoma disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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