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Advances in choroideremia

Gene therapy treatment set to enter the clinic

Dermot McGrath

Posted: Saturday, June 1, 2019


Dyon Valkenburg MD

With gene therapy for choroideremia approaching regulatory approval in the next few years, clinicians should start actively preparing their patients to benefit from this potentially sight-saving treatment, according to Dyon Valkenburg MD.

“Choroideremia will be treatable in the coming years, so we need to start selecting and preparing our patients now. There are still a lot of unanswered questions in terms of whether we will also provide this therapy for the worst affected female carriers, and also regarding the most opportune time to administer gene therapy. There are also wider societal questions relating to the cost-benefit of such treatments for the relatively small number of patients involved,” he told delegates attending the 9th EURETINA Winter Meeting in Prague.

Choroideremia is an X-linked, recessive disease resulting in progressive degeneration of the retina, the retinal pigment epithelium (RPE) and the choroid, Dr Valkenburg explained. Its prevalence is estimated to be approximately one in every 50,000-to-100,000 people.

“The choroideremia gene function encodes for Rab Escort Protein 1 (REP1), which is essential in intracellular trafficking, escort and prenylation. When the trafficking is disrupted, cell apoptosis occurs leading to remodelling of the affected retinal cells, with degeneration of choroid and RPE followed by photoreceptor loss,” he said.

In males, the condition gradually advances and starts with night blindness and eventually results in progressive loss of peripheral vision and total blindness in the late stages, although some extreme peripheral field detection may remain, said Dr Valkenburg.

Clinical diagnosis is based on characteristic fundus appearance with extensive chorioretinal atrophy and a residual island of retinal tissue in the posterior pole, defective dark adaptation, peripheral visual field loss, an electroretinogram pattern of rod-cone degeneration, and a family history consistent with X-linked inheritance.

Although X-linked diseases tend to occur in males, it is now well established that choroideremia may also present in female carriers, said Dr Valkenburg. He cited a recent study carried out at two clinical centres in the Netherlands and one in the United Kingdom that looked at the phenotype of 50 choroideremia carriers.

“Thirteen of the patients had night blindness, 18 had decreased visual acuity, and the median age at which visual acuity started to decline was 59.5 years. All had abnormalities on fundus autofluorescence imaging (FAF) which seemed to be more severe with age and six of them exhibited a male atrophy pattern,” he said.

The results of the first gene therapy clinical trial for choroideremia, carried out by Prof Robert MacLaren of Oxford, United Kingdom, which were first published early in 2014 showed very promising results, and surpassed the expectations of the researchers involved, noted Dr Valkenburg.

Prof MacLaren’s team used an adeno-associated virus-2 (AAV2) vector construct encoding REP1 to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells.

“Of the 12 patients who followed the protocol the visual acuity remained largely stable with a mean improvement of two or three ETDRS letters, and retinal sensitivity improved slightly, as did fixation. The results were very promising overall and indicate that the gene therapy may be able to halt the disease progression,” he said.

Although initial trials have helped to answer some of the fundamental questions relating to the safety of gene therapy in treating inherited retinal disease, more questions concerning the benefits of early intervention, optimal dosing, surgical technique and cost-benefit utility remain, said Dr Valkenburg.

“The long-term effect of gene therapy treatment is still unknown. The longest follow up in RPE65 related retinal disease is about nine years but it is still unknown if a single or multiple treatments need to be administered to sustain a long-term effect.

“Secondly, the cost-utility issue is still an issue for these therapies as they are very expensive and the quality-of-life gains may seem modest in relation to the expense incurred. So we need to ask ourselves as a society: what are we willing to pay for such therapies in the future?” he concluded.

Dyon Valkenburg: dyon.valkenburg@radboudumc.nl


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