US20200157158A1 - Modulation of Wnt5a to Treat Glaucoma - Google Patents
Modulation of Wnt5a to Treat Glaucoma Download PDFInfo
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- US20200157158A1 US20200157158A1 US16/752,677 US202016752677A US2020157158A1 US 20200157158 A1 US20200157158 A1 US 20200157158A1 US 202016752677 A US202016752677 A US 202016752677A US 2020157158 A1 US2020157158 A1 US 2020157158A1
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- intraocular pressure
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Definitions
- Glaucoma is a major health problem which affects over 3 million Americans and 60 million people worldwide. It is estimated that 111.8 million people will be affected by this disease worldwide in 2040. A major risk factor for this disease is increased intraocular pressure (IOP), which can damage the optic nerve and cause permanent blindness without treatment.
- IOP intraocular pressure
- Existing eye drops or oral medications are of limited efficacy with many side effects, and surgeries often fail with scar formation and fibrosis.
- Aqueous humor is the clear colorless liquid that fills the anterior and posterior chambers of the eye. It is produced by the ciliary body at the posterior chamber and exits the anterior chamber angle through the conventional pathway via trabecular meshwork and Schlemm's canal, and the nonconventional pathway via uveoscleral outflow. In normal eyes, a dynamic balance exists between the production and drainage of aqueous humor, maintaining IOP in the normal range.
- Schlemm's canal is a circumferential channel located at the iridocorneal angle in the ocular anterior chamber. It is part of the conventional aqueous humor outflow system, which accounts for 70-90% of the total aqueous humor that drains out of the eye in human.
- the endothelial cell lining of Schlemm's canal is one of the primary sites of resistance to aqueous humor drainage and is a major determinant of IOP.
- IOP When canal resistance increases with age or under pathological situation, IOP is elevated leading to glaucoma with irreversible optic nerve damage and vision loss. It is therefore an important target for glaucoma therapy.
- Wnt5a belongs to the Wnt family that comprises ligands and receptors in mammals.
- Wnt5a is expressed on Schlemm's canal, and its expression is regulated in response to sheer stress change. Moreover, by inhibiting Wnt5a, we can effectively lower IOP in vivo.
- the invention provides methods and compositions for locally treating glaucoma or pathogenic intraocular pressure.
- the invention provides a method of treating glaucoma or pathogenic intraocular pressure, comprising locally administering to an eye in need thereof a Wnt5a inhibitor.
- the invention provides an ophthalmic formulation of a Wnt5a-specific inhibitor selected from an antibody, an siRNA, an small interfering peptide, and a small molecule inhibitor, in unit dosage form for treating glaucoma or pathogenic intraocular pressure.
- the invention encompasses all combinations of the particular embodiments recited herein.
- the methods may be practiced with all disclosed compositions including specific embodiments.
- the disclosed Wnt5a inhibition methods can be genetic manipulation, and/or administrations of small interfering RNAs (siRNAs), antibodies, small molecules, etc, many of which are commercially available from sources like Applied Biological Materials Inc. (ABM, Richmond BC), Life Technologies (ThermoFisher Scientific), Sigma-Aldrich, etc.
- the methods can be used alone to lower intraocular pressure and to prevent or treat glaucoma, and/or in combination with other therapeutic approaches, such as eye drops, medications, laser, implanted devices, and surgery, etc. to prevent or treat glaucoma.
- Wnt5a is expressed on human primary SC cells in culture and mouse SC in vivo. Wnt5a expression is regulated with sheer stress change, as analyzed by quantitative real-time PCR assay. We also demonstrate that Wnt5a expression in human SC cells can be down-regulated by Wnt5a-specific siRNA, which affects SC cell functions as well.
- Wnt5a-specific siRNA which affects SC cell functions as well.
- Wnt5a knockout mice Compared with the control littermates that had IOP elevation at all time-points studied, Wnt5a knockout mice only showed elevated IOP at the early (within 24 hours) but not later time points, indicating an unsustainable IOP increase with Wnt5a intervention.
- wnt5a intervention is effective in protecting retinal nerve fiber layer and increasing SC permeability, a target for enhancement of aqueous movement through the conventional outflow system to manage ocular hypertension (e.g. Tam et al., Scientific Reports 7:40717, DOI: 10.1038/srep40717).
- Wnt5a is an effective therapeutic target for glaucoma management.
- Wnt5a specific siRNA was obtained commercially (human WNTSA siRNA, Life Technologies; Anastas, et al. J. Clin. Investig. 2014, 124, 2877-2890).
- subconjuctival injection of siRNA is performed as described by Yuen et al. (2014, Invest Ophthalmol Vis Sci. 2014; 55:3320-3327).
- Mice are randomly selected to receive subconjunctival injection of 5 uL (0.2 lg/uL) siRNA or control twice a week for 2 weeks.
- intracameral injection of siRNA is performed as described by Tam et al.
- mice are anaesthetized by intra-peritoneal injection, and pupils are dilated.
- a pulled blunt-ended micro-glass needle is first used to puncture the cornea to withdraw aqueous humour Immediately after puncture, a pulled blunt-ended micro-glass needle attached to a 10 ⁇ l syringe is inserted through the puncture, and 1.5 ⁇ l of PBS containing 1 ⁇ g siRNA is administered into the anterior chamber. Contralateral eyes receive an identical injection of 1.5 ⁇ l containing the same concentration of scrambled siRNA.
- intraocular hypertension was induced in the right eye (OD) of wildtype normal mice and Wnt5a neutralizing antibodies were administered to assess their therapeutic effects on IOP and other parameters of glaucoma including corneal edema, retinal ganglion cell (RGC) death, and RNFL thinning
- IOP in Wnt5a antibody treated eyes was significantly lower and maintained at the baseline level.
- Wnt5a intervention reduced corneal edema, as measured by central corneal thickness in vivo by OCT. Increased corneal thickness was observed in the control group after IOP was increased, but not in Wnt5a antibody treated eyes.
- Wnt5a intervention reduced RGC death as well as RNFL thinning in the treated eyes. These were detected by immunostaining and OCT, respectively. These results confirmed that topical Wnt5a antibody intervention significantly lowers IOP and protects the cornea and retina in a mouse model of glaucoma.
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Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16/752,677 US20200157158A1 (en) | 2017-08-20 | 2020-01-26 | Modulation of Wnt5a to Treat Glaucoma |
| US18/522,141 US20240124538A1 (en) | 2017-08-20 | 2023-11-28 | Modulation of Wnt5a to Treat Glaucoma |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762547854P | 2017-08-20 | 2017-08-20 | |
| PCT/US2018/046578 WO2019040311A1 (en) | 2017-08-20 | 2018-08-14 | MODULATION OF WNT5A TO TREAT GLAUCOMA |
| US16/752,677 US20200157158A1 (en) | 2017-08-20 | 2020-01-26 | Modulation of Wnt5a to Treat Glaucoma |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2018/046578 Continuation WO2019040311A1 (en) | 2017-08-20 | 2018-08-14 | MODULATION OF WNT5A TO TREAT GLAUCOMA |
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| CA2729889A1 (en) * | 2000-02-29 | 2001-09-07 | Alcon, Inc. | Screening method for frizzled related proteins agonists and antagonists |
| CN1652743A (zh) * | 2002-04-17 | 2005-08-10 | 大正制药株式会社 | 毛发生长补剂 |
| KR100881058B1 (ko) * | 2007-07-06 | 2009-01-30 | 부산대학교 산학협력단 | Ｗｎｔ５ａ 단백질의 억제제를 포함하는 신경교아종 치료및 예방용 조성물 |
| WO2012158910A2 (en) * | 2011-05-18 | 2012-11-22 | The Regents Of The University Of California | Compositions and methods for treating retinal diseases |
| EP2554662A1 (en) * | 2011-08-05 | 2013-02-06 | M Maria Pia Cosma | Methods of treatment of retinal degeneration diseases |
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| Edwards et al., Journal of Molecular Biology, 334:103-118, 2003. * |
| Hanaki et al., Mol Cancer Ther 11(2):298-307, Feb 2012, Supplementary Data, pages 1-17. * |
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| WO2022266270A1 (en) * | 2021-06-18 | 2022-12-22 | The Regents Of The University Of California | Treatment of Glaucoma by Neuroprotection |
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| CN117379543A (zh) | 2024-01-12 |
| EP3668487A4 (en) | 2020-08-26 |
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| JP7299889B2 (ja) | 2023-06-28 |
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| CN117159718A (zh) | 2023-12-05 |
| JP2023099171A (ja) | 2023-07-11 |
| KR20200042912A (ko) | 2020-04-24 |
| CN111132664A (zh) | 2020-05-08 |
| WO2019040311A1 (en) | 2019-02-28 |
| CN117159463A (zh) | 2023-12-05 |
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