A new gene therapy approach to treat retinitis pigmentosa (RP) has been discovered by researchers from Trinity College Dublin and University College London (UCL), who teamed up to pool their expertise in genetics, virology and ophthalmology.
RP is a group of rare genetic disorders that involve a breakdown and loss of cells in the retina. Common early stage symptoms include difficulty seeing at night and a loss of side (peripheral) vision, with blindness often developing in time.
The first inherited retinal disease (IRD) patient was treated in 2007 and in November 2017, the first direct-to-human gene therapy in the world (Luxturna) was approved for Leber Congenital Amaurosis (a form of IRD). Luxturna, which delivers the correct version of the mutated RPE65 gene to the retina, may be available in Australia by the end of the year. However the RPE65 gene is just one of more than 260 genes that may be responsible for IRDs.
Targeting RP2 Mutations
Scientists have known for some time that mutations in the gene ‘RP2’, which is responsible for making a protein essential for normal vision, are also associated with RP diseases. However, there are currently no therapies to treat people living with a number of RP diseases.
The collaborative team behind the new research used a modified common virus to deliver a normal, functioning copy of the RP2 gene into ‘mini retinas’, which had been engineered from stem cells and which contained the defective version of the gene. The mini retinas developed in UCL simulated the RP2 disease in patients.
Subsequent analysis showed that these mini retinas had successfully taken up the functioning RP2 gene following the viral delivery and produced the essential protein associated with it.
Crucially, the treated mini retinas showed significant improvement – underlining that the approach had rescued them from RP.
Ciara Shortall, PhD Researcher in Trinity’s School of Genetics and Microbiology, and one of the main authors of the published study explained the significance of the work.
“For the last 30 years there has been a lot of buzz about gene therapies and their potential for treating a huge variety of debilitating diseases and disorders, but it is really only recently that science has overcome difficulties associated with such approaches and begun to bring potential therapies far closer.
analysis showed that these mini retinas had successfully taken up the functioning RP2 gene following the viral delivery and produced the essential protein associated with it
“In relative terms it is now fairly easy to replace troublesome genes with functioning versions using non-harmful viruses, which is what we have done here. And while we are still some time and a lot of work away from an approved therapy, it is hugely exciting to have begun a journey that could one day provide an effective treatment to rescue eyesight.”
The Trinity team, led by Professor Jane Farrar, used their expertise in genetics and virus creation in the process, while the UCL team, led by Professor Michael Cheetham, took the lead in creating the mini retinas used to road-test the gene therapy.
Professor Cheetham said, “It is an important development that we can now reproduce so many elements of inherited disease using these mini-retinas. It makes it possible for us to study in detail why people go blind and try to find ways to prevent blindness. It’s exciting that the gene therapy seems to be so effective for this form of RP.”
The study was published in Stem Cell Reports.
Optometry at Centre of Research
Speaking recently at Optometry Western Australia’s virtual conference WAVE@home, Australia’s Dr Lauren Ayton, said ocular gene therapy for eye disease is “huge” and optometry would be at its centre.
“It’s gone from the sphere of science fiction to reality very quickly… The eye is the perfect place for gene therapy: there is no direct blood supply to the retina, there are no lymphatics within the eye and the eye has immune deviant properties which mean gene therapies delivered to the eye are more likely to last.
“Anything we inject into the eye will not enter the systemic blood stream and the retinal cells do not divide after birth, so if you can treat the retina then the transgene expression may persist indefinitely and will not be diluted.”
Dr Ayton recommended that optometrists and ophthalmologists offer access to clinical trials to patients who have IRD or age related macular degeneration and an interest in associated research.
“This will help us further our knowledge in the research field and give them access to early treatments,” Dr Ayton said.
Optometrists who are interested in pursuing this should contact their local research institution, such as the Centre for Eye Research Australia (Melbourne; www. cera.org.au), Lions Eye Institute (Perth; www.lei.org.au), Save Sight Institute (Sydney; www.savesightinstitute.org.au) or an academic within their local University School of Optometry.
Lane et al., Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids, Stem Cell Reports (2020), https://doi.org/10.1016/j.stemcr.2020.05.007