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An international consortium report the largest, longest and comprehensive natural history study of choroideremia – a rare X-linked degenerative retinopathy.

An international consortium of clinical researchers, led by Prof. Robert MacLaren, based in Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, UK, has reported a natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness.  According to the researchers, “to our knowledge, this is the largest, longest, and most comprehensive single prospective natural history study of CHM”.  The study found that changes from baseline in retinal sensitivity, central EZ area (central ellipsoid zone area), and total area of FAF (fundus autofluorescence) “could be more sensitive identifiers of early CHM than BCVA decline in natural disease progression”. Using these outcomes as endpoints in future interventional clinical studies, these could help identify novel therapies for early CHM that could slow progression prior to the increased BCVA decline.

Robert MacLaren, MB ChB DPhil FRCOphth FRCS FACS FMedSci, Professor of Ophthalmology, University of Oxford, Consultant Vitreoretinal Surgeon and Fellow of Merton College.

Choroideremia (CHM) is an X-linked retinal degeneration that impacts an estimate of 1/50,000 males worldwide, exhibiting retinal thickening, photoreceptor degeneration, RPE depigmentation, and retinal remodelling.  Males develop nyctalopia in their teens progressing to a loss of peripheral visual field leading to profound blindness in the fifth and sixth decades. CHM encodes Rab Escort Protein 1 (REP-1) which is a ubiquitously protein required for geranylgeranylation of ras-related GTPases, or Rab proteins, trafficking of vesicles in endocytic and exocytic pathways.  Currently, there are several gene therapy studies focused on CHM treatment using both primary and secondary outcomes.  In the natural study research, male patients with genetically confirmed CHM and visible active disease within the macular region, aimed to evaluate the primary outcome of the change in BCVA over time at months 4, 8, 12, 16, and 20. In addition, a range of functional and anatomical secondary outcome measures were assessed up a year, including retinal sensitivity, central ellipsoid zone area, and total area of fundus autofluorescence.

The results of the current study showed that a total of 220 participants completed the study. The mean BCVA was stable over 20 months and most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > -5 ETDRS letters at Month 20. Interocular symmetry was low overall and reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; -0.68 dB, -0.48 dB), central EZ area (anatomical outcome; -0.276 mm2, -0.290 mm2), and total area of FAF (anatomical outcome; -0.605 mm2, -0.533 mm2).  According to the researchers, there results presented a “unique, non-interventional study aimed to clarify the natural history of this rare disease by following participants over 20 months. A secondary aim sought to identify which outcomes would be the most sensitive to use as endpoints for monitoring disease progression in an interventional study”. Finally, the researchers high-lighted that the utility of BCVA as an endpoint to follow early CHM progression is limited however, there other outcomes may be valuable as endpoints in future interventional clinical studies to help identify novel therapies in the coming years, aimed to reduce the patient burden and economic burden of the disease.