Figure 7. Schematic representation of Lca5^+/gt (HET), Lca5^gt/gt (HOM), and gene therapy–treated photoreceptors.

In unaffected HET photoreceptors (left), lebercilin (LCA5; orange) localizes predominantly at the proximal part of the bulge region, between CEP290 (cyan, at the level of the Y-links) and RP1 (gray, distal axonemal protein). IFT81 (yellow) localizes to the same bulge proximal region as LCA5, but also accumulates above the basal body and to a lesser extent along the CC. In HOM photoreceptors (middle), the CC is extended, as illustrated by an elongated CEP290 and POC5 (green) signal. Furthermore, bulge formation and distal axoneme organization is disrupted, leading to rhodopsin (RHO, bright green) mis-trafficking, with accumulation above the basal body, localization along the CC, and inside vesicle-like structures. Moreover, LCA5 loss leads to decreased levels of IFT81 and RP1 at the bulge region and more dispersed localization along the distal axoneme. AAV-LCA5 gene augmentation therapy (right) partially restores bulge formation, CC and distal axoneme organization, as well as RP1 and rhodopsin localization. IFT81 localization is restored to a lesser extent, possibly explained by the ectopic LCA5 expression along the distal axoneme.