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Editors Selection IGR 9-1

Basic Science: Pathophysiology

Comment by Paul Kaufman on:

74403 Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma, Kim J; Park DY; Bae H, Journal of Clinical Investigation, 2017; 127: 3877-3896

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This long and complex paper¹ in the Journal of Clinical Investigation from September 2017 is a challenging read, especially for those not well-versed in mouse genetics. Nonetheless, the experimental crosses are logically and clearly designed, the structural and functional data are clear and are correctly interpreted, and the findings and conclusions are eye opening. One must remember, of course that these are mice, not monkeys or humans, and time is measured in weeks, not years and decades. That said, the authors demonstrate convincingly that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for Schlemm's canal (SC) formation, is also indispensable for maintaining SC integrity during adulthood.

Signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for Schlemm's canal (SC) formation, is also indispensable for maintaining SC integrity during adulthood

Deletion of Angpt1/Angpt2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, aqueous humor outflow (AHO), and Prox1 activity. These functions diminish in the SC during aging, leading to impaired SC structural integrity and transcytosis. Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged mice. The authors conclude that the Angpt-Tie 2 system is essential for SC integrity, and that the impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma in humans.

The authors did not discuss the pitfalls of extrapolating directly from mice to humans, and there is a long, long drive between this paper and a therapeutic intervention of any sort. Nonetheless, some of these genetic linkages are seen in some primary congenital glaucoma patients and families, giving credence at least to the development story, so stay tuned for the follow-ups to this stellar tour-de-force work.

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