21 September, 2023
This is a summary of the webinar held on Tuesday 8th August, 2023, featuring two of Retina Australia’s recent research grant recipients. You can also view a video recording of this event here.
RNA base editing strategies as potential therapeutic of inherited retinal dystrophies
Associate Professor Rick Liu from the Centre for Eye Research in Melbourne spoke about his team’s work on RNA base editing and its potential as a therapeutic for inherited retinal disease (IRD).
While Luxturna has been highly successful in treating Leber’s Congenital Amaurosis (LCA) by introducing a normal version of the RPE65 gene into the eye using an adeno-associated virus (AAV) vector, treatment for many other IRDs will not be possible using this technology, as around 45% of the up to 300 different genes that cause IRDs are too large to be delivered by AAVs.
Neuroprotective effect of SAHA in Retinitis Pigmentosa. Do time and frequency matter?
Our second speaker was Annie Miller, a PhD candidate from the Lions Eye Institute in Perth. She presented the results of work done looking at the suitability of a gene independent treatment for Retinitis Pigmentosa (RP).
Currently these solutions are being tested in the laboratory rather than being available as actual treatments. They include things such as retinal prosthesis, cell therapies and pharmaceuticals that can prevent the cell loss that happens in these diseases.
In RP, the rod and cone cells die due to a number of different processes, and once they are dead they can’t regenerate. One of the causes of these deaths is thought to be the accumulation of a molecule called cGMP, which leads to the accumulation of other molecules through a cascade effect and results in cell death. One of these molecules is called HDAC or histone deacetylase. It is thought that an increase of HDAC in the cell due to the RP mutation can lead to the cell death.
This project focused on the development of a broad treatment approach that could be used on RP patients by investigating the effect of an FDA-approved HDAC inhibitor (SAHA) to protect photoreceptor cells, especially cones, from degeneration in two mouse models of RP, the autosomal recessive model (rd1) and the autosomal dominant model (RhoP23H/+).
The intraocular administration (via injection to the eye) of SAHA to the mice was tested once the photoreceptors had started degenerating but some were still present. In the rd1 mouse model, which degenerates very quickly, results showed that the drug did rescue some of the peripheral photoreceptor cells but did not rescue the central photoreceptors, likely as they were too far degenerated already. While SAHA potentially has a net protective effect in the retina of these mice, the effects of the drug seem to wane over time.
The work done in the RhoP23H/+ model of RP is still preliminary with their lab group currently working on more experiments. However, their preliminary data showed positive results, showing that administration of SAHA at 2 months old allows for a significant protection of the photoreceptors four days after treatment.
Future work will focus on quantification of cone numbers after treatment, and assessing whether multiple injections of SAHA will increase the period of effectiveness of the drug. The team is also planning to study the neuroprotective effects in other mouse models of IRDs, e.g. Achromatopsia models, as HDAC has been implicated in a number of different IRDs.
You can read the full details of this research project here.