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Vahitha Shameem Nizamudheen, Xianghong Shan, Ishaq Ahmed Viringipurampeer, Emran Bashar, Xia Wang, Cheryl Y Gregory Evans; Novel therapeutic strategies to rescue the developmental abnormalities in aniridic glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3967.
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© ARVO (1962-2015); The Authors (2016-present)
Aniridia syndrome is a rare congenital birth that is progressive and leads to blindness. Here we tested two novel therapeutic approaches (ex vivo gene therapy and nonsense suppression) to target the glaucoma phenotype associated with aniridia in the Pax6Sey/+ haploinsufficient aniridia mouse model. Tgfb2 is a direct downstream target of Pax6, necessary for the development of the anterior chamber structures of the eye.
Full length mouse Tgfβ2 cDNA was cloned into the pIRES-DsRed2 expression vector. Adipose-derived mesenchymal stem cells (MSCs) were electroporated with the Tgfβ2 expression vector driven by a CMV promoter. Approximately 50,000 Tgfβ2-secreting MSCs were injected into the anterior chamber of the Pax6Sey/+ mouse eye (N=5) at postnatal day 5 (P5). Expression of Tgfβ2 was analyzed by ELISA and immunohistochemistry at P21 and P45. Structural benefits were assessed by TEM. Either an aqueous suspension of Ataluren was injected subcutaneously, or Ataluren-containing eyes drops were instilled twice daily from P5 - P45 (N=5 each). Efficacy of nonsense suppression was assessed by histology and immunocytochemistry.
In the cell-based approach, we observed the complete formation of Schlemm’s canal (SC) and a partially repopulated trabecular meshwork (TM). ELISA demonstrated an increase in the concentration of the Tgfβ2 in the treated groups. Nonsense suppression via the topical route rescued the iridocorneal angle defects of TM and SC better than systemic drug administration.
Nonsense suppression therapy is an effective method to rescue developmental abnormalities caused by Pax6 nonsense mutations. The cell-based approach would be an option to treat the iridocorneal abnormalities caused by Pax6 frameshift and missense mutations.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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