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Xia Wang, Olena Sivak, Andrew Metcalfe, Kevin Gregory-Evans, Cheryl Y Gregory-Evans; Pharmacological nonsense suppression therapy in Rpe65-/- mouse model of Leber congenital amaurosis reverses the retinal functional deficits in vivo. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):256.
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© ARVO (1962-2015); The Authors (2016-present)
Leber congenital amaurosis (LCA) is an inherited eye disease where more than 400 mutations in 19 different genes have been identified. This extensive genetic heterogeneity is a major barrier to the development of therapeutics. Most LCA patients have in common severe visual impairment diagnosed within the first few years of life. This disease is characterized by severe and early vision loss, sensory nystagmus, and an un-recordable electroretinogram (ERG). In LCA approximately 35% of gene mutations are in-frame nonsense mutations. We hypothesized that nonsense suppression therapy from early pre-and post-natal stages, using the small molecule drug Ataluren, could be used in treating the Rd12 mouse model of LCA that harbors a homozygous in-frame nonsense mutation in the Rpe65-/- mouse to improve the ocular phenotype.<br />
Rpe65-/- time-mated pregnant mice received daily subcutaneous injections of Ataluren (30 µg/g) from E12.5 until birth. The offspring then received daily injections from P4 to P60, P90, or P120. For postnatal treatment only, newborn mice received injections from P4 and continued to P60 or P90. Drug efficacy was tested in vivo by electrophysiology and optokinetic tracking responses.<br />
Early prenatal treatment coupled with postnatal injections of Ataluren resulted in optokinetic tracking spatial threshold frequencies of 0.4-0.5 cycles/degree at P90 and P120, equivalent to that in normal mice. However, optokinetic tracking did not show a normal threshold frequency in newborn Rpe65-/- mice that received postnatal treatment only. Untreated Rpe6-/- mice exhibited reduced b-wave amplitudes in dark-adapted ERG response and a delayed light-adapted ERG response. However, the prenatally treated mice showed ~50% increase in characteristic dark-adapted rod responses, dark oscillatory potentials, and photopic cone responses at P120.<br />
Pharmacological delivery of nonsense suppression therapy beginning in the prenatal period stably reversed the functional defects observed in the Rpe65-/- mutant eye, suggesting that it is possible to correct developmental abnormalities of the retina using a targeted drug therapy. Nonsense suppression may provide a novel treatment option for LCA patients through safe, non-invasive drug delivery that maybe also relevant to other childhood ocular birth defects.
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