ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma

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  • Kavita Praveen
  • Gaurang C. Patel
  • Lauren Gurski
  • Ariane H. Ayer
  • Trikaladarshi Persaud
  • Matthew D. Still
  • Lawrence Miloscio
  • Tavé Van Zyl
  • Silvio Alessandro Di Gioia
  • Ben Brumpton
  • Kristi Krebs
  • Bjørn Olav Åsvold
  • Esteban Chen
  • Venkata R. M. Chavali
  • 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
  • Tybjærg-Hansen, Anne
  • Cristen Willer
  • Scott Waldron
  • Sabrina Walley
  • Hua Yang
  • Sarthak Zaveri
  • 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. Yancopoulos
  • Aris Baras
  • Carmelo Romano
  • Giovanni Coppola
  • Regeneron Genetics Center
  • GHS-RGC DiscovEHR Collaboration
  • Estonian Biobank Research Team

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.

TidsskriftCommunications Biology
Antal sider15
StatusUdgivet - 2022

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