ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma
Disease areas:
brain
eye
Last updated:
Author(s):
Goncalo R. Abecasis, Michael Cantor, Andrew Deubler, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Katherine Siminovitch, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mona Nafde, Sean O'Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Kathie Sun, Amelia Averitt, Nilanjana Banerjee, Sameer Malhotra, Deepika Sharma, Jeffery C. Staples, Ashish Yadav, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher Gillies, Hyun Min Kang, Michael Kessler, Jack Kosmicki, Nan Lin, Daren Liu, Adam Locke, Jonathan Marchini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Charles Paulding, Carlo Sidore, Kyoko Watanabe, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Michelle G. LeBlanc, Jason Mighty, Lyndon J. Mitnaul, Nirupama Nishtala, Nadia Rana
Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.
1. The primary scientific goal of the research is to apply human genetics to the identification of new drug targets, the validation of existing targets…
Institution:
Regeneron Genetics Center, LLC, United States of America
