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Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3) are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess safety and effectiveness of symmetric and asymmetric occluders in perventricular device closure without cardiopulmonary bypass of perimembranous ventricular septal defects (pmVSDs). METHODS: The present retrospective study enrolled 581 patients who underwent perventricular device closure of pmVSDs under transoesophageal echocardiography guidance from May 2011 to April 2016, and outpatient electrocardiography and transthoracic echocardiography assessments at 1, 3, 6 and 12 months, and yearly thereafter. RESULTS: The overall success rate of device implantation was 92.6% (43 surgical conversions immediately). Between patients receiving symmetric (n = 353) and asymmetric (n = 185) occluders, there were no significant differences in age, weight and defect diameter distributions; however, both before discharge and at mean 28.6 ± 21.2 (range, 1-60)-month follow-up, the symmetric group had lower rates of trivial residual shunt (5.7% vs 11.4%, P = 0.018; and 0.8% vs 5.9%, P = 0.001) and bundle branch block (0.8% vs 5.4%, P = 0.002; and 0.6% vs 3.8%, P = 0.009); and at follow-up, the asymmetric group had lower residual shunt (47.6% vs 85.0%, P = 0.020) and similar branch block (30.0% vs 33.3%, P = 1.000) disappearance rates. There were no severe complications, i.e. aortic regurgitation, malignant arrhythmias, haemolysis or device dislocation. CONCLUSIONS: Perventricular device closure of pmVSDs appears safe and effective with symmetric and asymmetric occluders. However, the lower residual shunt disappearance and higher branch block incidence rates for asymmetric occluders would favour more proactive conversion to surgical repair immediately when residual shunt is present intraoperatively. [ABSTRACT FROM AUTHOR]