Gene therapy of retinal dystrophies: achievements, challenges and prospects.

Early attempts at gene therapy of inherited retinal diseases by recombinant adenovirus-vectored gene replacement in laboratory animals met with moderate success but the effect was transient. Recently, emphasis has shifted to less toxic vectors, namely recombinant adeno-associated (rAAV) viruses. Ribozymes, targeted to the P23H rhodopsin mutation in transgenic rats, significantly reduced photoreceptor loss and slowed attenuation of the electroretinogram (ERG) for 8 months. By gene replacement, rAAV-based photoreceptor rescue has been achieved in the rds-/- mouse and has restored vision in dogs carrying a RPE65 gene mutation. Minigenes for neurotrophins delivered by rAAV have been effective in achieving structural rescue of photoreceptors in rodent models of dominant disease, although this has not always been accompanied by functional rescue. One of the current challenges is the application of ribozyme therapy for dominant mutations coupled with wild-type gene augmentation to overcome haploinsufficiency. Other animal models are currently being utilized for preclinical studies as well. Spontaneously mutated Irish Setters and rd mice offer excellent subjects for the therapy of recessive mutations as do the RPE65 knockout mouse and RCS (rdy) rat. With burgeoning preclinical successes, the future looks bright for the treatment and cure of inherited retinal diseases in human patients.