Does gene therapy always have to be gene-specific?

Early 2020 marked an important milestone for the Retina UK community, when the first person with an inherited retinal condition received NHS treatment to potentially slow or even stop the progression of their sight loss.

The treatment was Luxturna, a gene replacement therapy, which provides the retina with healthy copies of a gene called RPE65. However, Luxturna can only work for those whose sight loss is caused by faulty RPE65 in the first place, and these individuals number less than 100 in the UK. A small number of other gene therapies are in clinical testing, but again, they almost always target a specific gene. With over 300 different genes potentially responsible for inherited retinal conditions, that leaves a huge number in our community without a treatment option within reach.

Researchers are investigating other approaches, such as cell-based therapies, which have the potential to work regardless of the causative genetic fault. But are there particular genes that, when injected into the back of the eye like Luxturna, can overcome a myriad of underlying problems?

Cone rescue

There are two types of light-sensing photoreceptor cells in the retina: rod cells, which are concentrated in the periphery of the retina and tend to degenerate early in the course of retinitis pigmentosa; and cone cells, which are found in the middle of the retina and are responsible for detailed central vision. More than ten years ago, scientists discovered that rod photoreceptors produce a substance that is vital for the survival of cone photoreceptors, and named it rod-derived cone viability factor (RdCVF). As rod cells are lost in retinitis pigmentosa, the amount of RdCVF declines significantly, and the cones eventually suffer as a result.

Biotechnology company Sparing Vision is now investigating the possibility of boosting RdCVF levels in RP via a gene therapy approach, with the ultimate aim of preserving central vision for much longer, no matter what the underlying genetic fault. The Sparing Vision treatment provides copies of the genetic instructions for building RdCVF, which are then used by photoreceptors and other retinal cells to ramp up production. The RdCVF genes are packaged in harmless viruses and delivered via subretinal injection, just like Luxturna, but have the potential to exert beneficial effects regardless of the disease-causing gene. Sparing Vision is hoping to begin early phase clinical trials in France and the USA in late 2022.

The company also has another gene therapy approach in preclinical development, this time using a gene that can “jump start” cones that have already partially degenerated. In the long term, Sparing Vision aims to combine the two approaches in the hope of restoring some lost vision and prolonging the therapeutic effect.

Re-setting retinal cells

Meanwhile, a US company called Ocugen is hoping that one particular gene, called NR2E3, might have the power to re-set and stabilise retinal cells that have been damaged by a number of different underlying genetic faults.

NR2E3 is what’s known as a modifier gene, which can significantly affect disease outcomes, impacting onset, rate of progression, and severity by influencing key biological networks. Studies in five unique mouse models of retinal degeneration, all with different genetic faults, showed that NR2E3 gene therapy rescued photoreceptors from further damage after disease onset.

Ocugen has started an early phase clinical trial of this therapy in 18 people with RP caused by mutations in NR2E3 itself or in the RHO (rhodopsin) gene. Ultimately, they hope to test the treatment across a broad range of genetic diagnoses. The current trial is taking place at seven sites in the USA.

These two examples demonstrate the potential for gene therapy to make a broader impact. Thanks to your generous support, Retina UK will continue to fund researchers making key discoveries that underpin progress in treatment development.