Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerations

PRL Delta E1, a retina-specific isoform of prolactin, is expressed in multiple and diverse forms of canine inherited retinal degeneration (IRD). We find that while PRL Delta E1 expression in rods is not associated with the initial phase of disease characterized by acute photoreceptor cell death, it is associated with the protracted phase of slow cell loss. Restoration of photoreceptors to a healthy state by gene-specific replacement therapy of individual IRDs successfully suppresses PRL Delta E1 expression. Moreover, short-term PRL Delta E1 silencing using shRNA results in preservation of outer nuclear layer thickness, suggesting PRL Delta E1 drives retinal disease. However, longer-term observations reveal off-target toxic effects of the PRL Delta E1 shRNA, precluding determination of its full therapeutic potential. Future research efforts aimed at enhancing the safety and specificity of PRL Delta E1-targeting strategies may identify a potential universal intervention strategy for sustaining photoreceptors during the prolonged phase of multiple IRDs.