PDE6A gene therapy trial report: the importance of scientific learnings in an unsuccessful trial
Researchers from the University Hospital Tübingen in Germany recently announced that there were no signs of visual gains in an early-phase clinical trial of a PDE6A gene therapy for Retinitis Pigmentosa (RP).
What is RP?
RP is one of the most common types of inherited retinal disease (IRD), associated with faults in over 100 genes. It is estimated that faults in the PDE6A gene accounts for around 1% of individuals with recessive RP.
RP causes progressive vision loss, starting peripherally, due to the loss of light-sensing photoreceptor cells in the retina. There are two types of photoreceptors, cones and rods, which differ in structure, function and location. To learn more, please watch this short animation video on Inherited Retinal Disease.
The treatment:
AAV8.hPDE6A is an adeno-associated viral vector gene therapy delivered via a subretinal injection. This means that a small virus, that doesn’t cause illness in humans, is used as a delivery system to introduce or alter genetic material within cells. This approach is based on similar principles used in the approved treatment for RPE65-related RP, Luxturna.
The PDE6A gene provides the instructions for making part of a protein that is essential for ‘resetting’ the rod cell after it detects light so that it can respond properly again.
Faults in the PDE6A gene can cause disruptions in the internal chemical signalling of rod cells, leading to chemicals building up in the cell. These chemicals cause stress to the rod cells and over time they degenerate. When rods degenerate, cones are also affected over time.
AAV8.hPDE6A is designed to target the rod photoreceptors, delivering a healthy version of the PDE6A gene. This will allow for normal production of the essential protein, restoring rod health and preventing the degeneration of cone cells.
The trial:
The early phase clinical trial involved 9 participants, each receiving 1 subretinal injection of the treatment. 6 participants received a lower dose and 3 participants received the higher dose.
The findings:
The primary endpoint in this trial was safety, with secondary outcomes including changes in best-corrected visual-acuity, colour perception and visual fields among others. These outcomes were measured over a 12-month period.
They found:
- No meaningful visual gains after 12-months
- Slight thinning of the central retina
- Small areas of thinning in the peripheral retina
- Difficulty in distinguishing colours
- Moderate decline in visual acuity
- No serious general health problems caused by the treatment
However, it should be noted that due to the naturally slow progression of PDE6A-related RP, a 12-month follow up may not be long enough to show any desired effects on slowing vision loss.
What now?
Whilst the trial did not show the desired outcomes as predicted by earlier testing in animal models, it provides important information for the continuation of research in this field. By identifying aspects that could be improved, such as the dosage or delivery method, and the side effects that could occur, this trial helps to guide research towards safer, more effective therapy trials in the future.