Project 6: Generation & Characterisation of Sustained Release Ocular Implants for Neuroprotective Drug Efficacy
There is an unmet clinical need to develop effective treatments for blindness due to retinal dysfunction. Notably, in Europe, 0.7 million citizens are considered blind and an additional 34 million citizens affected by vision loss. This translates to 123 million workdays lost per year and an annual economic cost to European society of €7.1 billion. At a personal level, patients are impacted by loss of independence (e.g. driving, reading, writing) and inability to recognize loved ones. Retinal diseases are the most common cause of childhood blindness worldwide (Gilbert et al. 2001).
Rare inherited retinal degenerations affect 1/3000 of the population. Research on these rare conditions has proven very informative to understand the mechanism of more common diseases such age-related macular degeneration which worldwide affects one in ten over the age of 50. Thus, improving therapeutic outcomes for blinding eye diseases represents a clinical challenge and a commercial opportunity.
An approach to preserve or restore vision is to identify neuroprotective drugs that prevent loss of visual function (Scholl et al 2016, Zhang et al. 2012). As neuroprotectants can modulate cell survival or cell death pathways common to all retinal disease, they have potential widespread applicability, irrespective of the risk factor. Recently, we demonstrated that phenotype-based visual behaviour assays in zebrafish can identify drugs preventing loss of visual function (Ward et al. 2019, Daly et al. 2017). Significantly, pathway analyses demonstrated visual restoration was mediated by brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signaling, a known neuroprotective pathway in mammalian eyes (Daly et al 2017). Notably, a small molecule BDNF mimetic was sufficient to restore visual function in zebrafish models of blindness. Key advances going forward are to identify additional effective analogs and to generate sustained release ocular implants (Galvin et al. 2016) for lead neuroprotectant BDNF mimetics by encapsulation into (hyaluronan) microparticles/needles.
Key Objectives in this PhD project are:
- To manufacture sustained release nano/micro-particle formulations of lead neuroprotective drugs and to characterise their physiochemical properties.
- To characterise the in vitro release profile of the formulations over a 6-12 month period and to validate the bioactivity of the released drug.
- To characterise the safety of the sustained release formulations
- To determine if the sustained ocular release formulation preserves visual function in pre-clinical models of blindness