oxadiazoles and Aniridia

Congenital aniridia is a severe ocular abnormality characterized by incomplete formation of the iris and many other ocular complications. Most cases are caused by the paired box 6 (PAX6) gene mutations generating premature termination codons (PTCs).. Ophthalmic examination was performed on a Chinese pedigree with congenital aniridia. The mutation was identified by targeted next-generation sequencing. Nonsense suppression therapy was applied on patient-derived lymphocytes. The PAX6 expression was assayed by real-time polymerase chain reaction and Western blot.. Complete aniridia was complicated with horizontal nystagmus, contract, foveal hypoplasia, and microphthalmia. A novel heterozygous c.702_703delinsAT (p.Tyr234*) mutation was found in exon 9 of PAX6, generating a PTC at the homeodomain. There were about 50% reductions of both full-length PAX6 protein and PAX6 mRNA in patient-derived lymphocytes, indicating haploinsufficiency due to nonsense-mediated mRNA decay. Ataluren (PTC124) and geneticin (G418) could induce about 30%-40% translational readthrough. Nonsense suppression therapy restored PAX6 protein to about 65%-70% of unaffected family controls.. Our data expanded the genetic and phenotypic variations of congenital aniridia, and showed the therapeutic effect of nonsense suppression on this disease using patient-derived cells.

Topics: Adult; Aniridia; Cells, Cultured; Child; Female; Gentamicins; Haploinsufficiency; Heterozygote; Humans; INDEL Mutation; Male; Middle Aged; Nonsense Mediated mRNA Decay; Oxadiazoles; PAX6 Transcription Factor; Pedigree

Aniridia is a panocular disorder that severely affects vision in early life. Most cases are caused by dominantly inherited mutations or deletions of the PAX6 gene, which encodes a transcription factor that is essential for the development of the eye and the central nervous system. In this issue of the JCI, Gregory-Evans and colleagues demonstrate that early postnatal topical administration of an ataluren-based formulation reverses congenital malformations in the postnatal mouse eye, providing evidence that manipulation of PAX6 after birth may lead to corrective tissue remodeling. These findings offer hope that ataluren administration could be a therapeutic paradigm applicable to some major congenital eye defects.

Topics: Animals; Aniridia; Eye Proteins; Gentamicins; Homeodomain Proteins; Oxadiazoles; Paired Box Transcription Factors; PAX6 Transcription Factor; Repressor Proteins

Aniridia is a congenital and progressive panocular condition with poor visual prognosis that is associated with brain, olfactory, and pancreatic abnormalities. Development of aniridia is linked with nonsense mutations that result in paired box 6 (PAX6) haploinsufficiency. Here, we used a mouse model of aniridia to test the hypothesis that manipulation of Pax6 dosage through a mutation-independent nonsense mutation suppression strategy would limit progressive, postnatal damage in the eye. We focused on the nonsense suppression drugs 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (ataluren) and gentamicin. Remarkably, we demonstrated that nonsense suppression not only inhibited disease progression but also stably reversed corneal, lens, and retinal malformation defects and restored electrical and behavioral responses of the retina. The most successful results were achieved through topical application of the drug formulation START (0.9% sodium chloride, 1% Tween 80, 1% powdered ataluren, 1% carboxymethylcellulose), which was designed to enhance particle dispersion and to increase suspension viscosity. These observations suggest that the eye retains marked developmental plasticity into the postnatal period and remains sensitive to molecular remodeling. Furthermore, these data indicate that other neurological developmental anomalies associated with dosage-sensitive genetic mutations may be reversible through nonsense suppression therapeutics.

Topics: Animals; Aniridia; Chemistry, Pharmaceutical; Codon, Nonsense; Cornea; Eye Proteins; Gene Dosage; Gentamicins; Homeodomain Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxadiazoles; Paired Box Transcription Factors; PAX6 Transcription Factor; Repressor Proteins; Retina; Visual Acuity