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Inherited retinal disease

Research is slowly unlocking the secrets of ABCA4 in retinal disease

Dermot McGrath

Posted: Tuesday, July 9, 2019

Researchers have identified a number of promising therapeutic strategies for a range of retinal diseases associated with mutations in the ABCA4 gene, some of which are entering human trials in the next few years, according to Caroline Klaver MD, PhD.

“The ABCA4 gene is one of the most implicated genes in retinal dystrophies and it is also a bit further ahead of any of the other genes in terms of potential therapies. It is very important to register patients with ABCA4-related disease into a national database so they can be evaluated for inclusion in future trials, many of which will be commencing over the next few years,” she told delegates attending the 9th EURETINA Winter Meeting in Prague.

The ABCA4 gene is a complex molecule that is part of the family of ATP-binding cassette (ABC) transporters and is expressed exclusively in retina photoreceptor cells, explained Dr Klaver.

Mutations in ABCA4 lead to accumulation of A2E, a toxic lipofuscin fluorophore, resulting in atrophy of the retinal pigment epithelium (RPE) and death of the photoreceptor cells. Many blinding diseases are associated with these mutations including Stargardt’s disease, cone-rod dystrophy, retinitis pigmentosa (RP) and increased susceptibility to age-related macular degeneration.

“The gene has a very important and complex role in the visual cycle. It transports vitamin A and suppresses accumulation of A2E. When it does not function well there is an accumulation of toxic A2E, which eventually causes the RPE cell to die after lipofuscin deposits are formed. That whole process can be suppressed by rearing the photoreceptor cell in darkness or by inhibiting the RPE65 gene,” she said.

Although Stargardt’s disease used to be considered a juvenile macular dystrophy, that definition no longer holds true, Dr Klaver noted.

“It most commonly presents in the second or third decade of life but some cases present really late, after the age of 75. We know that these cases are not just AMD because these patients have mutations in the ABCA4 gene. In general, the later the onset the better the prognosis. The earlier the onset the much harder the diagnosis can be in terms of phenotype because there are so few distinguishing features to identify. The classic textbook Stargardt’s disease is usually intermediate onset with characteristic yellow-white flecks on fundus autofluorescence (FAF) imaging, and a progressive bilateral visual loss,” she said.

While electroretinogram (ERG) testing is not commonly performed in Stargardt patients, it can prove useful as a prognostic tool, said Dr Klaver.

“Recent studies have shown that ERG abnormalities worsen prognosis, and the progression of RPE atrophy goes faster for these patients. Most of the late-onset Stargardt has some form of foveal sparing but it can develop to severe visual impairment after the diagnosis,” she said.

A number of novel interventions are currently under investigation to treat Stargardt’s disease, including stem cell therapies, gene therapy and pharmacological approaches, said Dr Klaver.

Human embryonic stem cells (hESC) transplantation has shown potential as a treatment option for Stargardt’s disease. Two prospective phase I/II studies in the United States reported good safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt’s disease, with further trials planned in the near future.

In terms of gene therapy, the SAR422459 trial, previously known as StarGen, uses a lentivirus as the vector to deliver the corrected ABCA4 gene into the host cell. The Phase I/IIa dose-escalation trial is currently ongoing at centres in France and the United States.

A number of pharmacological agents are also under development, many focusing on the prevention of lipofuscin accumulation associated with Stargardt’s disease, said Dr Klaver.

The most advanced of these is emixustat, which is currently undergoing a phase III clinical study of 160 patients at 30 sites worldwide. Emixustat modulates the visual cycle by inhibiting RPE65 and slowing the visual cycle to reduce the availability of vitamin A derivatives to form precursors of A2E and related compounds.

Another compound currently entering phase II trials is remofuscin, which targets the harmful lipofuscin in the RPE cell, concluded Dr Klaver.


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