Purpose: The angiopoietin-1 (ANG1)-TIE signaling pathway orchestrates the development and maintenance of the Schlemm's canal (SC). In this study, we investigated the impact of adeno-associated virus (AAV)-mediated gene therapy with cartilage oligomeric matrix protein-ANG1 (COMP-ANG1) on trabecular outflow pathway.
Methods: Different serotypes of AAVs were compared for transduction specificity and efficiency in the anterior segment. The selected AAVs encoding COMP-ANG1 or ZsGreen1 (control) were delivered into the anterior chambers of wild-type C57BL/6J mice. The IOP and ocular surface were monitored regularly. Ocular perfusion was performed to measure the outflow facility and label flow patterns of the trabecular drainage pathway. Structural features of SC as well as limbal, retinal, and skin vessels were visualized by immunostaining. Ultrastructural changes in the SC and trabecular meshwork were observed under transmission electron microscopy.
Results: AAV-DJ could effectively infect the anterior segment. Intracameral injection of AAV-DJ.COMP-ANG1 lowered IOP in wild-type C57BL/6J mice. No signs of inflammation or angiogenesis were noticed. Four weeks after AAV injection, the conventional outflow facility and effective filtration area were increased significantly (P = 0.005 and P = 0.04, respectively). Consistently, the area of the SC was enlarged (P < 0.001) with increased density of giant vacuoles in the inner wall (P = 0.006). In addition, the SC endothelia lay on a more discontinuous basement membrane (P = 0.046) and a more porous juxtacanalicular tissue (P = 0.005) in the COMP-ANG1 group.
Conclusions: Intracamerally injected AAV-DJ.COMP-ANG1 offers a significant IOP-lowering effect by remodeling the trabecular outflow pathway of mouse eyes.
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http://dx.doi.org/10.1167/iovs.63.13.15 | DOI Listing |
J Physiol Sci
January 2025
Laboratory of Regulation in Metabolism and Behavior, Faculty of Agriculture, Kyushu University, 744 Motooka, Nishi-Ku, 819-0395, Fukuoka, Japan. Electronic address:
Intraocular pressure (IOP) plays a crucial role in glaucoma development, involving the dynamics of aqueous humor (AH). AH flows in from the ciliary body and exits through the trabecular meshwork (TM). IOP follows a circadian rhythm synchronized with the suprachiasmatic nucleus (SCN), the circadian pacemaker.
View Article and Find Full Text PDFJCI Insight
January 2025
Gavin Herbert Eye Institute-Center for Translational Vision Research, Depar, University of California Irvine School of Medicine, Irvine, United States of America.
Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction, leading to neurodegeneration, is the pathological hallmark of primary open-angle glaucoma (POAG). Impaired axonal transport is an early and critical feature of glaucomatous neurodegeneration. However, a robust mouse model that accurately replicates these human POAG features has been lacking.
View Article and Find Full Text PDFMed Gas Res
June 2025
Glaucoma Service, Wills Eye Hospital, Philadelphia, PA, USA.
Glaucoma is a chronic optic neuropathy that causes characteristic visual field defects and is considered one of the leading causes of irreversible vision loss worldwide. Lowering intraocular pressure is the only proven treatment for glaucoma. Medical therapy is usually the first-line treatment for open-angle glaucoma and ocular hypertension.
View Article and Find Full Text PDFJpn J Ophthalmol
January 2025
Institute for Photon Science and Technology, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
Purpose: There is no established method for visualizing the three-dimensional (3D) structure of the aqueous humor outflow tract. This study attempted to visualize the 3D structures of porcine and human ocular tissues, particularly the aqueous humor outflow tract using a transparency reagent composed of 2, 2-thiodiethanol.
Study Design: Clinical and experimental.
Invest Ophthalmol Vis Sci
January 2025
Department of Ophthalmology, Duke Eye Center, Duke University, Durham, North Carolina, United States.
Purpose: To study the roles of tubulin acetylation and cyclic mechanical stretch (CMS) in trabecular meshwork (TM) cells and their impact on outflow pathway physiology and pathology.
Methods: Primary TM cell cultures were subjected to CMS (8% elongation, 24 hours), and acetylated α-tubulin at lysine 40 (Ac-TUBA4) was assessed by western blotting and immunofluorescence. Enzymes regulating tubulin acetylation were identified via siRNA-mediated knockdowns of ATAT1, HDAC6, and SIRT2.
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