Gene Therapy Shows Promise Restoring Sight In Patients With Rare Inherited Blindness

The disease is caused by mutations on the X chromosome. Because men have only one X chromosome, they will develop symptoms if they receive a faulty gene copy from their mother. Women need to inherit mutations on both sides to experience the disease. HQuality/Shutterstock

More than two years after receiving an intra-ocular injection of an experimental gene therapy agent, 14 people with a rare, previously untreatable form of inherited blindness have achieved sustained improvements in vision.

The landmark findings, published in the journal Nature Medicine, are the latest update in University of Oxford ophthalmologist Robert MacLaren’s decade-long quest to preserve sight in individuals with choroideremia, a condition characterized by progressive vision loss that begins in childhood. Choroideremia is caused by mutations in the gene on the X chromosome that encodes a protein called REP1. Without this protein, the non-regenerating photosensitive cells within the retina cannot function properly, and they begin to die prematurely as the individual ages.

As early leaders in the emerging field of gene-based ophthalmic medicine, Dr MacLaren’s team saw the potential of using a modified virus to deliver a working copy of the REP1 gene into the genome within choroideremia patients’ retinal cells, therefore theoretically restoring REP1 production permanently. (Eye diseases were a great place to perfect early gene therapy platforms because the organ’s tissues are separated from the rest of the body yet easily accessible.)

After a long process of perfecting their candidate treatment, the group began human trials back in 2011. An initial group of six patients received a single surgical injection of the REP1 gene-carrying viral vector into the tissue under the retina; their fellow eye was left untreated as a control. In 2016, Dr MacLaren and his colleagues – who formed the biotech company Nightstar Therapeutics to advance the candidate’s development – announced that two of the six not only showed a cessation of disease progression but also demonstrated significant improvement in vision in the treated eye: they were able to read three or more additional lines on a standardized vision chart than they had been able to before the injection.

These sight gains were maintained for at least 3.5 years.

In the current study, Dr MacLaren’s collaborators at Oxford, the NHS, University College London, Imperial College London, and other institutes reported the outcomes of 14 total participants – including the initial six – who had been followed for at least two years after receiving the gene therapy injections.

Overall, the patients’ treated eyes showed remarkable improvements over their control eyes, even the two who experienced adverse reactions early on.

"The early results of vision improvement we saw have been sustained for as long as we have been following up these patients and in several, the gene therapy injection was over 5 years ago. The trial has made a big difference to their lives,” Dr MacLaren said in a statement.

The median visual gain was 4.5 letters on the chart, and six patients were able to read more than 5 additional letters, aka more than an entire line. Untreated eyes lost a median of 1.5 letters during follow-up.

“The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late-stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted,” the authors concluded.

A phase three clinical trial – the last step before a drug can be approved by the FDA – is already underway. The first gene therapy to be approved for an inherited disease, Luxturna, treats a similar progressive retinal disease that is mediated by mutations in a gene called RPE65. It was given the green light for US distribution in December 2017.

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