Human Molecular Genetics Advance Access originally published online on December 12, 2008
Human Molecular Genetics 2009 18(5):931-941; doi:10.1093/hmg/ddn421
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ABCA4 disease progression and a proposed strategy for gene therapy
1 Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA 2 Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA 3 Howard Hughes Medical Institute and Department of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
* To whom correspondence should be addressed at: Scheie Eye Institute, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA 19104, USA. Email: cideciya{at}mail.med.upenn.edu
Received September 5, 2008; Revised November 5, 2008; Accepted December 9, 2008
Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene replacement therapy. All individuals with ABCA4-disease show macular degeneration, but only some are thought to progress to retina-wide blindness. It is currently not predictable if or when specific ABCA4 genotypes will show extramacular disease, and how fast it will progress thereafter. Early clinical trials of focal subretinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals with known disease-causing ABCA4 alleles, we defined retina-wide disease expression by measuring rod- and cone-photoreceptor-mediated vision. Serial measurements over a mean period of 8.7 years were consistent with a model wherein a normal plateau phase of variable length was followed by initiation of retina-wide disease that progressed exponentially. Once initiated, the mean rate of disease progression was 1.1 log/decade for rods and 0.45 log/decade for cones. Spatio-temporal progression of disease could be described as the sum of two components, one with a central-to-peripheral gradient and the other with a uniform retina-wide pattern. Estimates of the age of disease initiation were used as a severity metric and contributions made by each ABCA4 allele were predicted. One-third of the non-truncating alleles were found to cause more severe disease than premature truncations supporting the existence of a pathogenic component beyond simple loss of function. Genotype-based inclusion/exclusion criteria and prediction of the age of retina-wide disease initiation will be invaluable for selecting appropriate candidates for clinical trials in ABCA4 disease.