Adenovirus mediated genetic therapy for hereditary retinal degeneration

Academic Article


  • Purpose: Mutations in the βsubunit of the cGMP phosphodiesterase gene (βPDE) can cause a recessively inherited retinal degeneration in several species, including mice, dogs and humans. We tested the possibility of altering the course of retinal degeneration in the rd mouse and in the redl dog through subretinal injection of the recombinant replication-defective adenovirus, Ad.CMVβPDE. Methods: An E1, E3-deleted recombinant adenovirus containing the CMV promoter used to drive expression of the wild-type murine cDNA for βPDE was microinjected into the subretinal space. Contralateral eyes were injected with a /acZ-containing adenovirus or buffer alone. Eyes of additional rd mice were coinjected with Ad.CMVβPDE and Ad.2.5HRP£d-2, an adenovirus using the 2.5 kb region upstream to the human rhodopsin gene to drive expression of the human bd-2 cDNA (provided by D. Merry). Clinical assessment of retinal degeneration was made with indirect ophthalmoscopy. Expression of PDE was assessed with RT-PCR and by enzymatic assay. The rate of retinal degeneration was assessed through measurements of widths of photoreceptor layers as a function of time after birth (with and without treatment). Results; Results were similar in both species in that subretinal injection of Ad.CMVβPDE results in βPDE transcripts and increased PDE activity lasting months after the treatment. Histological studies in the red) dogs are pending. Co-injection ofbcl-2 with βPDE in the rd mouse enhanced the histological rescue observed with injection of βPDE alone. Variables affecting the success of the treatment include dose, accuracy of the injection and age at treatment. Conclusiops: The evidence of therapeutic effect with minimal toxicity in the rd mouse and redl dog supports the feasibility of treating an inherited retinal degeneration by somatic gene therapy. Supported by RO1 EY10820-01, 5T32 EY07131, RPB, FFB, the Pennsylvania Lions, V & P Mackall Trust and the F. M. Kirby Foundation. None.
  • Authors

    Author List

  • Bennett J; Acland G; Zeng Y; Huffman L; Bajwa R; Klatt L; Li Y; Maguire A
  • Volume

  • 38
  • Issue

  • 4