Predicting Abca4 Disease Progression: A Strategy for Gene Therapy

Abstract

Purpose: : ABCA4-associated retinal degenerations (RDs) are being considered for gene therapy. All individuals with ABCA4-RD show macular degeneration, but extramacular disease is currently not predictable. This study defines a predictive model for the natural history of retina-wide ABCA4 disease, and characterizes the severity contributed by each variant.

Methods: : Sixty-six patients with two known disease-causing ABCA4 variants were included. Retina-wide disease was defined by measuring rod- and cone-photoreceptor mediated vision. Preferred locus of fixation was documented and all psychophysical tests were adjusted to each individual’s preferred fixation locus. In a subset of patients, autofluorescence imaging was performed.

Results: : Independent segregation of the two alleles was demonstrated in 40/54 families. Ages at first visit ranged from 9 to 74 years (mean=35.9); in the majority, data were available from a second visit that occurred on average 8.7 years after the first visit. Disease expression could range from minor macular lipofuscin disturbance to severe retina-wide loss of rod and cone function. Serial measurements were consistent with a model wherein a plateau phase of variable length with normal extra-macular function was followed by initiation of retina-wide disease that progressed exponentially at a rate of 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. Under the assumption that each allele makes an independent and additive contribution to severity of the retina-wide disease, 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 missense alleles were found to cause greater severity of disease as compared to premature truncation alleles.

Conclusions: : Our results support the hypothesis that ~30% of missense ABCA4 mutations demonstrate a pathogenic component of disease that is beyond simple loss of function and thus may not benefit from gene augmentation therapy. We also provide methods and criteria for identifying appropriate candidates at appropriate ages for upcoming gene therapy trials that will aim to arrest ABCA4 disease progression.

Keywords: retinal degenerations: hereditary • retinal pigment epithelium • gene transfer/gene therapy