BOTU Previous Research

This project investigated the role of connexin43 in the loss of vascular integrity associated with diabetic retinopathy. The study showed that connexin43 hemichannel blockers can prevent molecular and vascular signs of diabetic retinopathy in a mouse model of the disease.

Funding

This project was funded by the Auckland Medical Research Foundation [1117015] and the Buchanan Charitable Foundation.

Project outputs

Journal articles:

• Mugisho OO, Rupenthal ID, Paquet-Durand F, Acosta ML, Green CR 2019. Targeting connexin hemichannels to control the inflammasome: The correlation between connexin43 and NLRP3 expression in chronic eye disease, Expert Opin. Ther. Tar. 23:855-863
• Mugisho OO, Green CR, Zhang J, Acosta ML, Rupenthal ID 2019. Connexin43 hemichannels: A potential drug target for the treatment of diabetic retinopathy, Drug Discov. Today 24:1627-1636
• Mugisho OO, Green CR, Squirrell DM, Bould S, Danesh-Meyer HV, Zhang J, Acosta ML, Rupenthal ID 2019. Connexin43 hemichannel block protects against the development of diabetic retinopathy signs in a mouse model of the disease, J. Mol. Med. 97:215-229
• Mugisho OO, Rupenthal ID, Squirrell DM, Bould SJ, Danesh-Meyer HV, Zhang J, Green CR, Acosta ML 2018. Intravitreal pro-inflammatory cytokines in non-obese diabetic mice: Modelling signs of diabetic retinopathy, PLoS ONE 13:e0202156
• Mugisho OO, Green CR, Zhang J, Binz N, Acosta ML, Rakoczy E, Rupenthal ID 2017. Immunohistochemical characterization of Connexin43 expression in a mouse model of diabetic retinopathy and in human donor retinas. Int. J. Mol. Sci. 18(12):2567

This project investigated Xentry, a small cell penetrating peptide derived from the N-terminal region of X-protein of the Hepatitis B virus, for efficient peptide delivery into retinal cells. Xentry targets syndecan-4 in blood vessel endothelia, one of our targets in the treatment of age-related macular degeneration, and is not taken up by blood cells reducing any off-target effects. This provides the potential to reduce drug dose and injection frequency, ultimately resulting in more efficient treatment of retinal inflammatory conditions. This technology is now licensed to OcuNexus Therapeutics. 

Funding

This project was funded by Buchanan Charitable Foundation. 

Project outputs

Journal articles:

• Coutinho FP, Green CR, Acosta ML, Rupenthal ID 2020. Xentry-Gap19 rapidly inhibits Connexin43 hemichannel opening at low concentrations especially as a result of hypoxic injury, Drug Deliv. Transl. Res. 10(3):751-765
• Coutinho FP, Green CR, Rupenthal ID 2019, Targeting drugs to diseased ocular cells. ONdrugDelivery 94:10-12

In this project, we developed a model that will help predict the pharmacokinetics of therapeutic formulations inside the eye. The model was built to match intraocular human geometry and physiology and allowed us to perform intravitreal drug elimination studies in an in vitro set up. The low cost, reusability and ability to undertake evaluations devoid of ethical constraints make this approach a desirable alternative to current in vivo models.

This project developed an ex vivo model to evaluate the penetration of various formulations into the ocular tissues after topical application. Such a model allows screening of ocular formulations at an early stage of development and could reduce the cost and complexity of testing routines currently used by the pharmaceutical industry.

Project outputs

Journal articles:

• Agarwal P, Craig JP, Krösser S, Eickhoff K, Swift S, Rupenthal ID 2019 Topical semifluorinated alkane-based azithromycin suspension for the management of ocular infections. Eur. J. Pharm Biopharm. 142:83-91
• Agarwal P, Scherer D, Günther B, Rupenthal ID 2018. Semifluorinated alkane based systems for enhanced corneal penetration of poorly soluble drugs, Int. J. Pharm.538: 119-129
• Agarwal P, Rupenthal ID 2016. In vitro and ex vivo corneal penetration and absorption models. Drug Deliv. Transl. Res. 6:634-647

This project investigated the use of ultrasound to improve the delivery of drugs to the retinal tissues by cavitation and acoustic streaming. A peptide drug was loaded into nanoparticle coated with hyaluronan for active targeting to retinal cells and delivery efficacy was tested with and without application of ultrasound. 

In this project we aimed to shine light into the eye to either solidify or activate an intravitreal implant to allow for sustained and controlled drug dosing. The light-cured implant was based on a modified polymer containing drug-loaded nanoparticles, while the light-activated system comprised barrier arm controlled microparticles.

• Bisht R, Jaiswal JK, Oliver VF, Eurtivong C, Reynisson J, Rupenthal ID 2017. Preparation and evaluation of PLGA nanoparticle-loaded biodegradable light-responsive injectable implants as a promising platform for intravitreal drug delivery. J. Drug Deliv. Sci. Tec. 40:142-56
• Bisht R, Jaiswal JK, Rupenthal ID 2017. Nanoparticle-loaded biodegradable light-responsive in situ forming injectable implants for effective peptide delivery to the posterior segment of the eye. Med. Hypotheses 103:5-9
• Bisht R, Jaiswal JK, Chen YS, Jin J, Rupenthal ID 2016. Light-responsive in situ forming injectable implants for effective drug delivery to the posterior segment of the eye. Expert. Opin. Drug Deliv. 13:953-962