Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia
Nonsense mutations leading to premature stop codons are common occurring in approximately 12% of all human genetic diseases. Thus, pharmacological nonsense mutation suppression strategies would be beneficial to a large number of patients if the drugs could be targeted to the affected tissues at the...
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doaj-a6ed6384546f4f6480f73742489fcc8c2020-11-24T22:43:56ZengElsevierMolecular Therapy: Nucleic Acids2162-25312017-06-017C41742810.1016/j.omtn.2017.05.002Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of AniridiaXia Wang0Kevin Gregory-Evans1Kishor M. Wasan2Olena Sivak3Xianghong Shan4Cheryl Y. Gregory-Evans5Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC V5Z 3N9, CanadaDepartment of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC V5Z 3N9, CanadaCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5A2, CanadaDepartment of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC V5Z 3N9, CanadaDepartment of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC V5Z 3N9, CanadaDepartment of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC V5Z 3N9, CanadaNonsense mutations leading to premature stop codons are common occurring in approximately 12% of all human genetic diseases. Thus, pharmacological nonsense mutation suppression strategies would be beneficial to a large number of patients if the drugs could be targeted to the affected tissues at the appropriate time. Here, we used nonsense suppression to manipulate Pax6 dosage at different developmental times in the eye of the small eye (Pax6Sey/+; G194X) mouse model of aniridia. Efficacy was assessed by functional assays for visual capacity, including electroretinography and optokinetic tracking (OKT), in addition to histological and biochemical studies. Malformation defects in the Pax6Sey/+ postnatal eye responded to topically delivered nonsense suppression in a dose- and time-dependent manner. Elevated levels of Mmp9, a direct downstream target of Pax6 in the cornea, were observed with the different treatment regimens. The lens capsule was particularly sensitive to Pax6 dosage, revealing a potential new role for Pax6 in lens capsule maintenance and development. The remarkable capacity of malformed ocular tissue to respond postnatally to Pax6 dosage in vivo demonstrates that the use of nonsense suppression could be a valuable therapeutic approach for blinding diseases caused by nonsense mutations.http://www.sciencedirect.com/science/article/pii/S2162253117301725nonsense suppressionPAX6Atalurentherapyaniridia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xia Wang Kevin Gregory-Evans Kishor M. Wasan Olena Sivak Xianghong Shan Cheryl Y. Gregory-Evans |
spellingShingle |
Xia Wang Kevin Gregory-Evans Kishor M. Wasan Olena Sivak Xianghong Shan Cheryl Y. Gregory-Evans Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia Molecular Therapy: Nucleic Acids nonsense suppression PAX6 Ataluren therapy aniridia |
author_facet |
Xia Wang Kevin Gregory-Evans Kishor M. Wasan Olena Sivak Xianghong Shan Cheryl Y. Gregory-Evans |
author_sort |
Xia Wang |
title |
Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia |
title_short |
Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia |
title_full |
Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia |
title_fullStr |
Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia |
title_full_unstemmed |
Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia |
title_sort |
efficacy of postnatal in vivo nonsense suppression therapy in a pax6 mouse model of aniridia |
publisher |
Elsevier |
series |
Molecular Therapy: Nucleic Acids |
issn |
2162-2531 |
publishDate |
2017-06-01 |
description |
Nonsense mutations leading to premature stop codons are common occurring in approximately 12% of all human genetic diseases. Thus, pharmacological nonsense mutation suppression strategies would be beneficial to a large number of patients if the drugs could be targeted to the affected tissues at the appropriate time. Here, we used nonsense suppression to manipulate Pax6 dosage at different developmental times in the eye of the small eye (Pax6Sey/+; G194X) mouse model of aniridia. Efficacy was assessed by functional assays for visual capacity, including electroretinography and optokinetic tracking (OKT), in addition to histological and biochemical studies. Malformation defects in the Pax6Sey/+ postnatal eye responded to topically delivered nonsense suppression in a dose- and time-dependent manner. Elevated levels of Mmp9, a direct downstream target of Pax6 in the cornea, were observed with the different treatment regimens. The lens capsule was particularly sensitive to Pax6 dosage, revealing a potential new role for Pax6 in lens capsule maintenance and development. The remarkable capacity of malformed ocular tissue to respond postnatally to Pax6 dosage in vivo demonstrates that the use of nonsense suppression could be a valuable therapeutic approach for blinding diseases caused by nonsense mutations. |
topic |
nonsense suppression PAX6 Ataluren therapy aniridia |
url |
http://www.sciencedirect.com/science/article/pii/S2162253117301725 |
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