Caldesmon transgene expression disrupts focal adhesions in HTM cells and increases outflow facility in organ-cultured human and monkey anterior segments

Gabelt, B’Ann T.; Hu, Yujie; Vittitow, Jason L; Rasmussen, Carol R.; Grosheva, Inna; Bershadsky, Alexander D.; Geiger, Benjamin; Borrás, Terete; Kaufman, Paul L.

doi:10.1016/j.exer.2005.12.002

Cited by 52 publications

(33 citation statements)

References 22 publications

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“…[11][12][13] Interference with TM/IWSC cellular contractility, and cell-cell or cell-extracellular matrix adhesion, whether by inhibiting the Rho kinase or myosin light-chain kinase cascades or by disrupting actin microfilaments (whether by direct disruption or inhibition of their assembly) can result in increased outflow facility in live nonhuman primates 10,14,15 and in both human and primate organ-cultured anterior segments. [16][17][18][19][20] Several Rho kinase inhibitor compounds are in development [21][22][23][24][25][26] aiming to lower IOP by targeting trabecular outflow. Another novel agent targeting the TM is latrunculin B (Lat-B), which originates from Latrunculia (now Negombata) magnifica, a sponge from the Red Sea.…”

Section: Introductionmentioning

confidence: 99%

Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle Glaucoma

Rasmussen¹,

Kaufman²,

Ritch³

et al. 2014

Trans. Vis. Sci. Tech.

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Methods: In this Phase I, multicenter, double-masked, randomized, placebocontrolled, ascending-dose study, subjects with bilateral OHT or early POAG (.22 mm Hg) received one of four concentrations of INS115644 (Lat-B ophthalmic solutions, 0.005%, 0.01%, 0.02%, or 0.05%) in one eye over 3 days (5 single-dose instillations, separated by 12 hours). One eye was randomly assigned to active drug, the other to placebo. IOP was measured prior to treatment initiation (day 0) and on days 1 and 3.Results: Baseline IOPs were 22.9 6 2.4 mm Hg and 23.5 þ 3.1 mm Hg in the 0.02% and 0.05% dose groups, respectively. At 4 hours post instillation of the first dose, 0.02% INS115644 reduced IOP from baseline (mean 6 SE) by 3.8 6 0.7 mm Hg (P ¼ 0.002) and 0.05% by 3.9 6 1.0 mm Hg (P ¼ 0.004). A maximum IOP decrease of 24% was noted at 4 hours after the fifth instillation of 0.02%. Adjusting for diurnal baseline and IOP in the contralateral, placebo-treated eye, the maximal 12-hour hypotensive effect was 4.0 6 0.5 mm Hg (adjusted mean 6 SE), a 17% decrease, following the fifth instillation of 0.02% (day 3). Adverse events were few and consisted mainly of mild redness, irritation, and a transient, clinically insignificant increase ( 2.5%) in central corneal thickness. Conclusions:In OHT or POAG patients, twice daily Lat-B significantly lowered IOP compared with contralateral, placebo-treated eyes, with few and mild ocular adverse events.Translational Relevance: Lat-B may be a potential therapeutic agent for glaucoma.

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Section: Introductionmentioning

confidence: 99%

Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle Glaucoma

Rasmussen¹,

Kaufman²,

Ritch³

et al. 2014

Trans. Vis. Sci. Tech.

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“…In as over-expression of proteins in corneal epithelium of patients with diabetes mellitus, but their application for inherited gene defects is discouraged [30,31]. Nevertheless, Ads have demonstrated transfection efficacy both in anterior [10,[32][33][34][35] and posterior eye segment [36][37][38][39].…”

Section: Delivery Systemsmentioning

confidence: 99%

Treatment of ocular disorders by gene therapy

Solinís

Pozo-Rodríguez

Apaolaza

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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“…This targeted transduction opens the door to delivery of therapeutic transgenes that can regulate aqueous humor outflow. On the basis of cell and organ culture and live animal data, the structures and biochemical=enzymatic pathways involved in cellular and tissue contractility=relaxa-tion, cell shape maintenance, cell-cell and cell-extracellular matrix (ECM) interactions (Honjo et al, 2001;Rao et al, 2001;Carr and Noisakran, 2002;Tian and Kaufman, 2005;Gabelt et al, 2006;Liu et al, 2007), and the Wnt signaling pathway (Wang et al, 2008) are examples of potential TM targets. Other gene therapy strategies with potential to lower IOP by targeting the TM or neighboring tissue include regulating matrix proteins in both conventional and uveoscleral pathways and expressing prostaglandin biosynthesis and response pathway components.…”

Section: Discussionmentioning

confidence: 99%

Prolonged transgene expression with lentiviral vectors in the aqueous humor outflow pathway of non-human primates

Poeschla¹,

Barraza²,

Rasmussen³

et al. 2008

Human Gene Therapy

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We injected lentiviral vectors into the eyes of live nonhuman primates to assess potential for glaucoma gene therapy. Anterior chambers of five cynomolgus monkeys were injected with green fluorescent protein (GFP)-encoding feline immunodeficiency viral vectors. The monkeys were monitored for in vivo transgene expression and clinical parameters. Their eyes were harvested 2-15 months postinjection for tissue analyses. All seven eyes injected with 1.0-2.0Â10 8 transducing units (TU) showed substantial GFP fluorescence in the trabecular meshwork (TM), which was observable even by goniophotographic monitoring for up to 15 months. Only the lowest dose (0.03Â10 8 TU) failed to result in TM fluorescence detectable in vivo, and five of the eight vectorinjected eyes continued to display substantial GFP expression when enucleated eyes were examined at 2, 7, or 15 months postinjection. Some transduced cells were also detected in the iris and ciliary body. Mild, transient postinjection inflammatory responses exceeding that induced by a control saline injection were observed, but vectors did not raise intraocular pressure and were well tolerated. The results demonstrate the first lentiviral vector transduction of the nonhuman primate aqueous humor outflow pathway and support application of the system to human glaucoma gene therapy.

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Caldesmon transgene expression disrupts focal adhesions in HTM cells and increases outflow facility in organ-cultured human and monkey anterior segments

Cited by 52 publications

References 22 publications

Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle Glaucoma

Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle Glaucoma

Treatment of ocular disorders by gene therapy

Prolonged transgene expression with lentiviral vectors in the aqueous humor outflow pathway of non-human primates

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