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Subspecialties Retina, Basic & Translational Research

A Retinoid a Day Keeps The Blindness Away


Leber congenital amaurosis (LCA) is an untreatable, nefarious, inherited disease that results in children growing up with visual impairment that can range from reduced vision to complete blindness. So far, sixteen genetic abnormalities that lead to the LCA pathology have been identified, with mutations in two of the genes that encode enzymes involved in the visual phototransducation pathway, RPE65 and LRAT, being the culprit behind many cases of LCA (1). In such cases, rods and cones are present, it’s just that the retinal pigment epithelium can’t regenerate the chromophore, 11-cis retinal, so no (or limited) rod or cone signaling occurs. Over time, these cells become dormant, and have been thought to (eventually) die.

In terms of treatment, gene therapy has shown early promise in restoring vision in patients with RPE65 mutations, but is neither proven nor available. A different approach, administering a synthetic retinoid intermediate in order to replace the missing 11-cis retinal has been proposed. The drug is QLT091001 (synthetic 9-cis-retinyl acetate), and results from a Phase Ib clinical trial of the drug has been published in the July issue of The Lancet (2).

The study involved 14 participants from around the world with LCA ranging in age from 6 to 38 years, and all had either RPE65 or LRAT mutations. Oral QLT091001 was administered daily for 7 days (at doses ranging from 10–40 mg/m2). The week-long regimen appeared to work: 10 of the 14 patients enrolled exhibited improvements of at least 20 percent in Goldmann visual field (GVF) areas, and six of the 14 had experienced at least a five-letter improvement in visual acuity. For some patients, these effects were long-lasting. Two years after the trial, three patients still had a sustained GVF response, and four had a sustained visual acuity response. Side effects were common, the most frequent being transient headaches and photophobia, but in general, QLT091001 therapy was well-tolerated.

Robert Koenekoop, Professor of Human Genetics, Pediatric Surgery and Ophthalmology at Montreal’s McGill University (and lead author of the study) said that, “By giving patients with RPE65 or LRAT mutations an oral retinoid intermediate (QLT091001) most patients’ vision improved rapidly.” It also turned out that rods and cones in the retina can be recovered from their dormant or dying state. Koenekoop explained, “We discovered that a certain portion of the retinal cells that were not working because of the lack of 11-cis retinal, could be woken up. Contrary to what was previously thought, children with LCA and defects in RPE65 or LRAT are not born with dead retinal cells; the cells can simply go dormant, and they can remain dormant for years before they eventually die. The oral drug we tested awakened these cells and allowed patients to see.” Here’s hoping the efficacy-safety profile remains favorable throughout the larger-scale clinical trials that will follow.

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  1. Online ‘Mendelian Inheritance in Man’ (OMIM) Leber Congenital Amaurosis, Type I; LCA1 -204000., accessed July 21, 2014.
  2. R.K. Koenekoop, R. Sui, J. Sallum, “Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial”, Lancet, Epub ahead of print (2014). doi:10.1016/S0140-6736(14)60153-7.
About the Author
Mark Hillen

I spent seven years as a medical writer, writing primary and review manuscripts, congress presentations and marketing materials for numerous – and mostly German – pharmaceutical companies. Prior to my adventures in medical communications, I was a Wellcome Trust PhD student at the University of Edinburgh.

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