TY - JOUR
T1 - Development of a translatable gene augmentation therapy for CNGB1-retinitis pigmentosa
AU - Occelli, Laurence M.
AU - Zobel, Lena
AU - Stoddard, Jonathan
AU - Wagner, Johanna
AU - Pasmanter, Nathaniel
AU - Querubin, Janice
AU - Renner, Lauren M.
AU - Reynaga, Rene
AU - Winkler, Paige A.
AU - Sun, Kelian
AU - Marinho, Luis Felipe L.P.
AU - O'Riordan, Catherine R.
AU - Frederick, Amy
AU - Lauer, Andreas
AU - Tsang, Stephen H.
AU - Hauswirth, William W.
AU - McGill, Trevor J.
AU - Neuringer, Martha
AU - Michalakis, Stylianos
AU - Petersen-Jones, Simon M.
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/7/5
Y1 - 2023/7/5
N2 - In this study, we investigate a gene augmentation therapy candidate for the treatment of retinitis pigmentosa (RP) due to cyclic nucleotide-gated channel beta 1 (CNGB1) mutations. We use an adeno-associated virus serotype 5 with transgene under control of a novel short human rhodopsin promoter. The promoter/capsid combination drives efficient expression of a reporter gene (AAV5-RHO-eGFP) exclusively in rod photoreceptors in primate, dog, and mouse following subretinal delivery. The therapeutic vector (AAV5-RHO-CNGB1) delivered to the subretinal space of CNGB1 mutant dogs restores rod-mediated retinal function (electroretinographic responses and vision) for at least 12 months post treatment. Immunohistochemistry shows human CNGB1 is expressed in rod photoreceptors in the treated regions as well as restoration of expression and trafficking of the endogenous alpha subunit of the rod CNG channel required for normal channel formation. The treatment reverses abnormal accumulation of the second messenger, cyclic guanosine monophosphate, which occurs in rod photoreceptors of CNGB1 mutant dogs, confirming formation of a functional CNG channel. In vivo imaging shows long-term preservation of retinal structure. In conclusion, this study establishes the long-term efficacy of subretinal delivery of AAV5-RHO-CNGB1 to rescue the disease phenotype in a canine model of CNGB1-RP, confirming its suitability for future clinical development.
AB - In this study, we investigate a gene augmentation therapy candidate for the treatment of retinitis pigmentosa (RP) due to cyclic nucleotide-gated channel beta 1 (CNGB1) mutations. We use an adeno-associated virus serotype 5 with transgene under control of a novel short human rhodopsin promoter. The promoter/capsid combination drives efficient expression of a reporter gene (AAV5-RHO-eGFP) exclusively in rod photoreceptors in primate, dog, and mouse following subretinal delivery. The therapeutic vector (AAV5-RHO-CNGB1) delivered to the subretinal space of CNGB1 mutant dogs restores rod-mediated retinal function (electroretinographic responses and vision) for at least 12 months post treatment. Immunohistochemistry shows human CNGB1 is expressed in rod photoreceptors in the treated regions as well as restoration of expression and trafficking of the endogenous alpha subunit of the rod CNG channel required for normal channel formation. The treatment reverses abnormal accumulation of the second messenger, cyclic guanosine monophosphate, which occurs in rod photoreceptors of CNGB1 mutant dogs, confirming formation of a functional CNG channel. In vivo imaging shows long-term preservation of retinal structure. In conclusion, this study establishes the long-term efficacy of subretinal delivery of AAV5-RHO-CNGB1 to rescue the disease phenotype in a canine model of CNGB1-RP, confirming its suitability for future clinical development.
KW - CNGB1
KW - adeno-associated virus
KW - dog
KW - electroretinography
KW - gene therapy
KW - nonhuman primate
KW - perifoveal chorioretinal atrophy
KW - retinitis pigmentosa
KW - short rhodopsin promoter
KW - spectral domain optical coherence tomography
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U2 - 10.1016/j.ymthe.2023.04.005
DO - 10.1016/j.ymthe.2023.04.005
M3 - Article
C2 - 37056049
AN - SCOPUS:85154587010
SN - 1525-0016
VL - 31
SP - 2028
EP - 2041
JO - Molecular Therapy
JF - Molecular Therapy
IS - 7
ER -