GENE THERAPY

Gene therapy strategies have the potential to revolutionise management of a number of inherited retinal diseases in the future, according to Bart P Leroy MD, PhD. Addressing delegates at the 13th EURETINA congress in Hamburg, Germany, Dr Leroy, Ghent University Hospital & Ghent University, Ghent, Belgium and The Children's Hospital of Philadelphia, PA, US, said that a number of clinical trials have started, or are scheduled to get under way in the near future, for diseases such as Leber congenital amaurosis (LCA), Stargardt disease, Usher syndrome, choroideraemia and achromatopsia.

“The eye has a lot of advantages from a geneticist’s point of view. We are capable of easily accessing the eye, it is a pretty straightforward procedure to implant the replacement gene and we can look and observe what is happening in relative safety because of the immune-privileged status of the eye,” he said.

For patients with incurable retinal disease, gene therapy represents a real hope that their visual function can be preserved or even improved, and that one day the disease progression might be slowed or even halted, said Dr Leroy. “Clearly we want to improve vision for patients first and foremost, which means an improved quality of life for them, but we can also reduce the cost of blindness to society which is extensive,” he said.

Dr Leroy said that much of the pioneering work was initially performed in LCA patients. At present, at least 19 different genes, mutations in which lead to different forms of LCA, have been identified, including the RPE65 gene, which accounts for 5-10 per cent of all LCA cases, he said. After successful proof-of-principle trials in the Briard dog model by Jean Bennett et al. over a decade ago, the first human gene therapy replacement trials for LCA began in 2008 when three groups, two in the US and one in the UK, reported success in RPE65- associated LCA using the adeno-associated viral (AAV2) vector (Bainbridge et al, 2008; Cideciyan et al, 2008; Maguire et al, 2008).

“The results of these three independent trials showed that the treatment was safe and successful. There was some improvement of vision but that was not the primary outcome of the trials. There are now at least six clinical trials for LCA with a total of between 40 and 50 patients currently, and apparently so far there have been no vector-related issues, so it seems safe to do,” he said.

Dr Leroy noted that the phase I trial of 12 patients carried out at the Children’s Hospital of Philadelphia, as well as a follow-up trial of 11 of these patients, showed that the results were sustainable over a six-year follow-up period. “We see increased light sensitivity and improved pupillary responses in most of the patients, as well as improvement of the visual acuity. While we are not making these patients see normally, we are vastly improving their quality of life,” he said.

After initial treatment of the first eye, visual improvement was also noted in the untreated other eye. “We think there are potentially two or more mechanisms at work here to explain this. First, the fact that the nystagmus has decreased probably also helps the visual acuity for the untreated better eye. Cerebral plasticity in the cerebral cortex may also account for some of the improvements prior to the treatment that we saw,” he said.

Other conditions

Dr Leroy said that there is a lot of excitement surrounding the trials for Stargardt macular dystrophy currently under way at Casey eye Institute at the Oregon Health and Science University in Portland, Oregon, US, and the Centre Hospitalier Nationale D’Opthalmologie des Quinze-Vingts in Paris, France.

“There are a lot more patients with Stargardt disease than LCA. Most of them appear in our clinics at their best ages for treatment, between 10 and 30 years of age, and so they are economically active and they could be seriously helped by gene replacement therapy,” he said. The same company behind the Stargardt trial, Oxford BioMedica, is also recruiting for trials of UshStat, its gene therapy targeted for the treatment of retinitis pigmentosa associated with Usher syndrome type 1B, said Dr Leroy.

Positive news has also been emerging from the first clinical trial in humans of a gene therapy for choroideraemia, an inherited retinal degenerative disease caused by a defective Rab escort protein-1 (REP1) gene. Starting in October 2011, a team at John Radcliffe Hospital in Oxford led by Prof Robert E MacLaren of Oxford University began treatment of the first of six patients using a modified AAV vector to deliver the replacement gene. “We are awaiting the first published results from the trial but all the indications are that the treatment has been safe and successful,” said Dr Leroy. These have in the meantime been published, and support a positive outlook on gene therapy in choroideraemia (www.thelancet.com Published online January 16, 2014 http:// dx.doi.org/10.1016/S0140-6736(13)62117-0).

As well as the first human trial for achromatopsia, which is scheduled to probably start next year, a phase III trial for RPE65-related LCA is also under recruitment at the Children’s Hospital of Philadelphia.