Eyes on the prize: the latest in retinitis pigmentosa gene therapies

In patients with retinitis pigmentosa, the photoreceptors in the eye that are responsible for converting light into signals sent to the brain don't function as they should, leading to degeneration of the retina and eventual blindness in adulthood. Interim data from an ongoing Phase I/II study has found low doses of a new gene therapy can improve vision for certain RP patients. Chloe Kent finds out more.


etinitis pigmentosa (RP) is a cluster of rare genetic visual impairments that lead to the breakdown and loss of cells in the retina, the light-sensitive tissue that lines the back of the eye. RP can lead to night blindness, loss of peripheral and central vision, and trouble seeing different colours. 

The condition, which is estimated to affect roughly one in 4,000 people, typically becomes progressively worse, with many patients transitioning from visually impaired to legally blind as they age.

Abnormalities in any one of more than 50 genes can cause RP, all of which are linked to the structure and function of the retina’s photoreceptors. Photoreceptors can be divided into rods, which are responsible for vision in low light, and cones, which provide vision in bright light. As they degenerate, this causes gradual loss of vision. 

Rods typically break down before cones, which is why night blindness can be one of the first tell-tale signs of RP. For a person with the condition, dimly lit rooms can slowly start to appear impossibly dark. Later on, blind spots develop in the peripheral vision, which gradually fuse together and cause tunnel vision. Central vision is the last area to be affected by RP and can take years or even decades to fully decline.

The inheritance patterns of the disease have been identified as autosomal dominant, where one copy of an altered gene in each cell is sufficient to cause the disorder; autosomal recessive, where both copies of a gene in each cell have mutations; maternally inherited variants caused by defects in the mitochondrial DNA; and X-linked, where the mutation is carried on the X chromosome.

X-linked retinitis pigmentosa (XLRP) is the most severe form of RP, in which both the rods and the cones of the retina function poorly, leading to total blindness rather than the partial blindness associated with other variations of the condition. Changes in at least six genes are thought to cause the X-linked form of RP, with mutations in the RPGR gene accounting for more than 70% of cases, amounting to up to 20% of RP cases across the board. 

Because it is carried on the X chromosome, the disease typically results in the demonstration of inheritance in men, while women will be unaffected and referred to as ‘carriers’ – however, some carriers still do go on to develop symptoms.

Janssen and MeiraGTx have now unveiled six-month data from an ongoing Phase I/II trial of an investigational gene therapy for XLRP, known as the adeno-associated virus retinitis pigmentosa GTPase regulator (AAV-RPGR). The promising therapy has been generally well tolerated and demonstrated significant improvements in vision and could be life changing for XLRP patients.

An important advancement in XLRP treatment

“XLRP is characterised by early onset visual field loss, with most patients progressing to blindness and associated loss of independence by young adulthood,” said trial investigator and University College London professor of ophthalmology Michel Michaelides in a statement. “Six-month data demonstrate AAV-RPGR may improve visual function in XLRP patients. Initial data also suggest treatment with AAV-RPGR has the potential to stabilise or slow progressive vision loss.”

AAV-RPGR is designed to deliver functional copies of the RPGR gene to the subretinal space during a surgical procedure, to improve and preserve visual function. Thus far, it has been administered to the ten participants in the study at low, intermediate or high doses via surgical subretinal delivery. The low and high groups both contained three participants, while the intermediate group contained four. 

Six-month data from this dose-escalation part of the study has found significant improvements in baseline retinal sensitivity when compared to untreated eyes in both the low and intermediate groups.

Six-month data demonstrate AAV-RPGR may improve visual function in XLRP patients.

This was measured through perimetry tests, standard-of-care measures of retinal function that reproducibly determine retinal sensitivity both cross-sectionally and longitudinally, providing an objective measure of disease progression over time. 

Significant differences have also been observed in central visual field progression rates between treated eyes and untreated eyes in both the low and intermediate cohorts. This was measured using a V30 test, which analyses the central 30° of the visual field.

The therapy has only been delivered to the most affected eye for each patient, with the other eye serving as an untreated control. This has allowed the researchers to bypass establishing a placebo group.

Efficacy signals have been observed at first post-treatment assessments at three months, with improvements generally sustained or increased at six months.

Michaeides said: “These results support AAV-RPGR as an important advancement in the treatment of XLRP, for which there is no currently available therapeutic option.”

Treating RP: an eye on the horizon

At this stage in the research, the main goal is to establish the best dosage or scheduling of a new drug or therapy, and a high dose has now been effectively ruled out due to its decreased effectiveness compared to low and intermediate doses. 

Inflammatory responses to therapy were observed in two out of three patients in the high dose group, which may have contributed to the therapy’s weaker performance in this cohort. The study participants’ inflammation was effectively managed with steroids, and other adverse events that occurred as a result of the procedure were resolved without intervention.

Data suggest AAV-RPGR has the potential to address some of the key functional manifestations of this severe disease.

The encouraging overall results have left Janssen and MeiraGTx hopeful about beginning a Phase III trial of AAV-RPGR. AAV-RPGR has been granted Fast Track and Orphan Drug designations by the US Food and Drug Administration and PRIME, ATMP and Orphan designations by the European Medicines Agency.

“We are pleased to share these encouraging initial results from our XLRP gene therapy trial and look forward to advancing this programme into a Phase III trial,” said MeiraGTx president and CEO Alexandria Forbes in a statement. “These early data suggest AAV-RPGR has the potential to address some of the key functional manifestations of this severe disease for which there is no currently available therapy.”

Patients with XLRP are currently left with few options other than try to accept the fact that their vision will slowly but surely slip away over the years. Vision aids and canes can go some way towards helping XLRP patients live more independently, but if a gene therapy like Janssen and MeiraGTx’s can help restore their vision – or, if administered early enough, prevent it deteriorating in the first place – then this could be life changing.

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