ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma

• DOI: 10.1038/s42003-022-03932-6
• Publication Date: 2022-10-03T12:03:17Z
• Authors: Kavita Praveen; Gaurang C. Patel; Lauren Gurski; Ariane H. Ayer; Trikaladarshi Per...; Matthew D. Still; Lawrence Miloscio; Tavé Van Zyl; Silvio Alessandro...; Ben Brumpton; Kristi Krebs; Bjørn Olav Åsvold; Esteban Chen; Venkata R. M. Cha...; Wen Fury; Harini V. Gudiseva; Sarah Hyde; Eric Jorgenson; Stephanie Lefebvre; Dadong Li; Alexander Li; James Mclninch; Brijeshkumar Patel; Jeremy S. Rabinowitz; Rebecca Salowe; Claudia Schurmann; Anne-Sofie Seidelin; Eli Stahl; Dylan Sun; Tanya M. Teslovich; Anne Tybjærg-Hansen; Cristen Willer; Scott Waldron; Sabrina Walley; Hua Yang; Sarthak Zaveri; ; ; Goncalo R. Abecasis; Michael Cantor; Andrew Deubler; Aris Economides; Luca A. Lotta; John D. Overton; Jeffrey G. Reid; Alan Shuldiner; Katherine Siminov...; ; Christina Beechert; Caitlin Forsythe; Erin D. Fuller; Zhenhua Gu; Michael Lattari; Alexander Lopez; Thomas D. Schleicher; Maria Sotiropoulo...; Louis Widom; Sarah E. Wolf; Manasi Pradhan; Kia Manoochehri; Ricardo H. Ulloa; ; Xiaodong Bai; Suganthi Balasubr...; 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 Reve...; 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; ; Lance J. Adams; Jackie Blank; Dale Bodian; Derek Boris; Adam Buchanan; David J. Carey; Ryan D. Colonie; F. Daniel Davis; Dustin N. Hartzel; Melissa Kelly; H. Lester Kirchner; Joseph B. Leader; David H. Ledbetter; J. Neil Manus; Christa L. Martin; Raghu P. Metpally; Michelle Meyer; Tooraj Mirshahi; Matthew Oetjens; Thomas Nate Person; Christopher Still; Natasha Strande; Amy Sturm; Jen Wagner; Marc Williams; ; Andres Metspalu; Mari Nelis; Reedik Mägi; Tõnu Esko; Ying Hu; Kristian Hveem; Olle Melander; Lili Milani; Stefan Stender; Joan M. O’Brien; Marcus B. Jones; Gonçalo R. Abecasis; Michael N. Cantor; Jonathan Weyne; Katia Karalis; Aris Economides; Giusy Della Gatta; Manuel A. Ferreira; George D. Yancopo...; Aris Baras; Carmelo Romano; Giovanni Coppola
• Keywords: Adult; Mice, Knockout; QH301-705.5; Glaucoma; Blindness; Article; Mice; 03 medical and health sciences; Angiopoietin-like Proteins; 0302 clinical medicine; Animals; Humans; Biology (General); Angiopoietin-Like Protein 7; Intraocular Pressure

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), risk factor for glaucoma, but most treatments do not directly target the pathological changes to increased IOP, which can manifest as medication resistance disease progresses. To identify physiological modulators we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements extended these findings an risk. We report identification functional characterization rare coding variants (including loss-of-function variants) ANGPTL7 associated reduction protection. validated human genetics mice establishing that Angptl7 knockout have lower (~2 mmHg) basal compared wild-type, trend towards also heterozygotes. Conversely, increasing murine levels via injection into mouse eyes increases IOP. show acute silencing adult lowers (~2-4 mmHg), reproducing observations mice. Collectively, our data suggest important homeostasis amenable therapeutic modulation help maintain healthy prevent onset or slow progression glaucoma.