Identification of drugs that can safely and effectively maintain visual function in models of inherited retinal degeneration

Inherited Retinal Degenerations (IRD) are a diverse group of conditions resulting in blindness. This is often traumatic to the affected patient and families, and can cause significant socio-economic impact. Gene or stem-cell therapy show promise as treatments for IRD. However, these approaches are hampered by high costs and treatment irreversibility. In contrast, drug treatment using neuroprotectants to delay/prevent retinal degeneration offers potential as a more cost-effective and reversible treatment.
Another problem is that IRD can result from defects in one of ~200 genes. Thus, some treatments may only be effective in patients with specific IRD. Identifying the drugs most effective in patients with specific gene defects is a challenge. However, an opportunity exists using the zebrafish model to identify the drugs most neuroprotective in zebrafish strains that display IRD. Zebrafish, are tropical fish, that like humans are vertebrates. In recent years, genetic technologies have created many zebrafish strains carrying IRD. For example, the zebrafish pde6c strain show inherited retinal degeneration similar to patients with defects in the human PDE6c gene. The small size (2-3 cm) of adult zebrafish enables hundreds of strains to be easily maintained in UCD. The miniature size of zebrafish larvae (2-3 mm) means it is easy to evaluate drugs in many samples. Previously, we showed that HDAC inhibitors can retain visual function in a zebrafish strain with IRD and similar effects were observed in mouse models and a clinical trial evaluating HDAC inhibitors for IRD is underway. Here, we seek to determine which neuroprotectants/HDACi are most effective in an extensive collection of IRD zebrafish, analyse the short-longer-term safety and efficacy of these neuroprotectants, and to validate their effectiveness in appropriate mouse IRD models. Identifying the groups most likely to benefit from HDACi based on the zebrafish/mouse models will direct treatments to the appropriate patients

Award Date
19 June 2014
Award Value
Principal Investigator
Dr Maria Meehan
Host Institution
Fighting Blindness
MRCG-HRB Joint Funding Scheme