ABCA4 disease progression and a proposed strategy for gene therapy

Abstract

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.

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

“…1B) (51,52), even though underlying genetic mutations are presumed to be expressed in all retinal cells of relevance. In mouse models, and their localized treatments with gene therapy, spatiotemporal gradients of natural disease progression are not often investigated.…”

Clinical and molecular genetic study of 12 Italian families with autosomal recessive Stargardt disease

“…Comparison of a series of patients in which various mutations were associated with the reference mutation has quantified the contribution of the mutations to phenotype and age of onset, and an algorithm to estimate age of onset (limited to the panel of mutations studied) has been proposed. Estimates showed a consistency better than a decade (Cideciyan et al, 2009).…”

“…Innovative approaches such as gene therapy and stem cells are also being explored, but clinical application is not imminent (Cideciyan et al, 2009;Molday et al, 2009;Dahlmann-Noor et al, 2010).…”

“…Although preliminary and fragmented, these studies have established that mutations in the active site of the nucleotide-binding domain 2 of the protein (for example, the mutation C2150Y) are the most severe, followed by large deletions leading to truncated proteins. Mutations responsible for single amino acid substitutions are linked to milder phenotypes with late onset and slow progression (Rozet et al, 1999;Briggs et al, 2001;Cideciyan et al, 2009).…”

“…The predictive model proposed by Cideciyan et al (2009) uses 2 mutations that give rise to a truncated protein as a reference. The mutations are associated with an intermediate age of onset of 10.7 years.…”