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Editors Selection IGR 12-1

Novel and experimental therapies: Gene therapy

Comment by Nils Loewen & James Kim on:

53147 Optimizing gene transfer to conventional outflow cells in living mouse eyes, Li G; Gonzalez P; Camras LJ et al., Experimental Eye Research, 2013; 109: 8-16

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The authors found serendipitously that an intracameral bolus of three to five microliters of replication defective adenoviral vectors ‐ termed 'virus' throughout the manuscript ‐ injected over three minutes resulted in improved trabecular meshwork (TM) transduction while other lab members observed more eGFP marker expression elsewhere. Other groups had started to favor intravitreal injections to allow slow vector diffusion to the anterior segment and less loss from reflux, a problem specific to small rodent eyes. Rodent models for outflow studies may allow to take advantage of the advanced tools for molecular biology and genetics in this species. Intracameral injections in mice with needles as small as 30 gauge are prone to reflux and leaving a needle in an eye just barely more than a few seconds is very difficult due to movements from breathing and heartbeat that cannot be prevented. It is remarkable that the authors succeeded in maintaining seal and needle stability for as long as 50 minutes. Unless artifacts from impaled cannulas, IOP during these perfusions was dangerously high ranging from 40 mmHg to 160 mmHg as summarized in Figure 5 that shows three continuous, slightly wavy IOP graphs deemed by the authors to be representative but without visible single data points. Such high IOP raises concerns about ischemic damage from non-perfusion and traumatic optic nerve injuries especially when maintained for more than 30 minutes as was the case for all eyes. It remains unclear on how many animals the author's recommendation is based on to use small, three-minute vector bolus applications. A different possible conclusion is that larger eyes with better compliance (less IOP increase per volume), e.g., of non-human primates or perfused anterior segments and vectors with TM transduction kinetics that have shown to favor TM may be more practical.

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