Increased vulnerability of photoreceptors to aberrant splicing highlight the utility of AON-based therapy for CEP290-LCA

Mutations in CEP290 account for the most common form of Leber congenital amaurosis (LCA), a severe, early onset retinal disorder, and are associated with numerous other ciliopathies such as Joubert, Meckel-Gruber, Senior-Loken, and Bardet Biedl syndromes. Disease-causing mutations occur throughout the length of CEP290 and it is thought that resulting phenotypes vary in severity and organ involvement depending on the amount of residual CEP290 function. The most common LCA-causing mutation in CEP290 (c.2991+1655A→G) is found in approximately 86% of patients, and causes aberrant splicing and introduction of a cryptic exon containing a premature stop codon. Alternative splicing occurs in some transcripts, but not all, and thus a fraction of full length CEP290 is still produced at levels that are seemingly sufficient to maintain function of other organ systems. This study, from the Cheetham lab asks the question—why are only photoreceptors, but not other cells in the kidney or CNS, affected by this mutation? (1). Using human iPSC-derived optic cups, Parfitt et al. determined that the basis for the retina’s increased sensitivity to the c.2991+1655A→G mutation is increased aberrant splicing in developed photoreceptors. In addition, they validated, using antisense morpholinos, the ability to block this aberrant splicing and restore photoreceptor function (1).