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6406337 
Journal Article 
Safety and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in CNGB3-Mutant Dogs 
Ye, GJ; Komáromy, AM; Zeiss, C; Calcedo, R; Harman, CD; Koehl, KL; Stewart, GA; Iwabe, S; Chiodo, VA; Hauswirth, WW; Aguirre, GD; Chulay, JD 
2017 
28 
4 
197-207 
English 
29020838 
Achromatopsia is an inherited retinal disorder of cone photoreceptors characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. Approximately 50% of cases are caused by mutations in the cone photoreceptor-specific cyclic nucleotide gated channel beta subunit (CNGB3) gene. Studies in CNGB3-mutant dogs showed that subretinal injection of an AAV vector expressing human CNGB3, which has 76% amino acid identity with canine CNGB3, driven by a 2.1 kb human red cone opsin promoter (PR2.1) and packaged in AAV5 capsids (AAV5-PR2.1-hCNGB3) rescued cone photoreceptor function, but at high doses was associated with an inflammatory response (focal chorioretinitis) consistent with immune-mediated toxicity. AAV vectors containing the PR2.1 promoter packaged in AAV5 capsids and expressing either the native canine CNGB3 (AAV5-PR2.1-cCNGB3) or the human CNGB3 (AAV5-PR2.1-hCNGB3) were evaluated at different dose levels in CNGB3-mutant dogs. The vector expressing canine CNGB3 achieved somewhat better rescue of cone function but unexpectedly was associated with a greater degree of retinal toxicity than the vector expressing human CNGB3. Very low-level T-cell immune responses to some AAV or CNGB3 peptides were observed in animals that received the higher vector dose. There was a more than twofold increase in serum neutralizing antibodies to AAV in one of three animals in the low-dose group and in two of three animals in the high-dose group. No serum anti-hCNGB3 antibodies were detected in any animal. The results of this study do not support the hypothesis that the focal chorioretinitis seen with high doses of AAV5-PR2.1-hCNGB3 in the initial studies was due to an immune response to human CNGB3. 
; Animals; Chorioretinitis/genetics; Chorioretinitis/pathology; Chorioretinitis/therapy; Color Vision Defects/genetics; Color Vision Defects/pathology; Color Vision Defects/therapy; Cyclic Nucleotide-Gated Cation Channels/genetics; Cyclic Nucleotide-Gated Cation Channels/therapeutic use; Dog Diseases/genetics; Dog Diseases/pathology; Dog Diseases/therapy; Dogs; Genetic Therapy; Genetic Vectors/therapeutic use; Humans; Immunity; Cellular/genetics; Opsins/genetics; Parvovirinae/genetics; Promoter Regions; Genetic/genetics; Retinal Cone Photoreceptor Cells/metabolism; Retinal Cone Photoreceptor Cells/pathology; Index Medicus/