Advancing gene therapy for children with sight loss 

In 2008, Professor James Bainbridge and colleagues published preliminary results of the first clinical trial of gene therapy for inherited blindness. It is an often cited example of how scientific research is successfully translated into clinical treatment for the benefit of patients.

Since then, the team have extended their research into various forms of Leber’s Congenital Amaurosis (LCA) and possible gene therapies. The researchers developed a way to help children with the severe genetic eye condition, using a virus to provide the missing DNA to their retina. 

Leber’s Congenital Amaurosis is a rare inherited retinal condition (with similarities to retinitis pigmentosa) and is the most common form of inherited sight loss in children. LCA causes the specialised light-sensing photoreceptor cells at the back of the eye to stop working properly which causes vision loss. 

There are at least 20 different forms of LCA (type 1 through to type 20) that have currently been identified. Each type of LCA is caused by a defect in a different gene important for normal visual function, these genes include RPE65 (LCA 2), AIPL1 (LCA 4); CEP290 (LCA 10) and RDH12 (LCA 13). Current gene therapy research is looking at ways to correct these defects and help restore or stop further loss of vision. 

Following the initial clinical trials, results published on RPE65 (LCA2) gene therapy in the New England Journal of Medicine on longer-term follow up demonstrated that improvements in vision can last for as long as three years. It also indicated that greater benefits can be expected with improvements in the efficiency of gene delivery.

In a significant development in February 2020, the NHS started to offer people with LCA2 a new gene therapy that restores eyesight. The treatment, voretigene neparvovec, inserts a working copy of RPE65 via a one-off injection below the retina. NHS England has bought the drug at a reduced cost, enabling the treatment to be offered to an estimated 86 people each year.

Another form of LCA is caused by defects in the gene AIPL1 (LCA4). It is a rarer form than RPE65 (LCA2) but is more severe and has an earlier onset. As LCA4 is so rare and with the treatment window so short, a conventional clinical trial is currently not feasible. 

Therefore, Professor Bainbridge and colleagues have sought to bring a potential treatment to patients through a special treatment gene therapy. This is where the key components of the treatment have been through rigorous clinical trials but the specific gene defect being targeted has not. 

In a world-first for this condition (AIPL1 LCA4), ophthalmic surgeon Mr Chien Wong, Great Ormond Street Hospital (GOSH), Royal Free and Moorfields consultant ophthalmologist, along with Professor Bainbridge performed the operation on a two-year-old at GOSH. Six-months later, both surgeons said they were encouraged by her progress.

The gene therapies that have been delivered have the potential to positively impact the future vision of the children. Importantly, the evidence gained from using this treatment and the following progress could also inform other rare as well as more common eye diseases. It would also provide confidence that intervening early in a rapidly progressing disease can be effective. 

It is powerful to see the translation of research from the bench through to clinical trials. While this can take a number of years, investment in gene therapy research is resulting in some exciting developments in the field.