TY  - JOUR
PY  - 2016//
TI  - A targeted inhibitor of the alternative complement pathway accelerates recovery from smoke-induced ocular injury
JO  - Investigative ophthalmology and visual science
A1  - Woodell, Alex
A1  - Jones, Bryan W.
A1  - Williamson, Tucker
A1  - Schnabolk, Gloriane
A1  - Tomlinson, Stephen
A1  - Atkinson, Carl
A1  - Rohrer, Bärbel
SP  - 1728
EP  - 1737
VL  - 57
IS  - 4
N2  - PURPOSE: Morphologic and genetic evidence exists that an overactive complement system driven by the complement alternative pathway (AP) is involved in pathogenesis of age-related macular degeneration (AMD). Smoking is the only modifiable risk factor for AMD. As we have shown that smoke-related ocular pathology can be prevented in mice that lack an essential activator of AP, we ask here whether this pathology can be reversed by increasing inhibition in AP. <br><br>METHODS: Mice were exposed to either cigarette smoke (CS) or filtered air (6 hours/day, 5 days/week, 6 months). Smoke-exposed animals were then treated with the AP inhibitor (CR2-fH) or vehicle control (PBS) for the following 3 months. Spatial frequency and contrast sensitivity were assessed by optokinetic response paradigms at 6 and 9 months; additional readouts included assessment of retinal morphology by electron microscopy (EM) and gene expression analysis by quantitative RT-PCR. <br><br>RESULTS: The CS mice treated with CR2-fH showed significant improvement in contrast threshold compared to PBS-treated mice, whereas spatial frequency was unaffected by CS or pharmacologic intervention. Treatment with CR2-fH in CS animals reversed thinning of the retina observed in PBS-treated mice as analyzed by spectral-domain optical coherence tomography, and reversed most morphologic changes in RPE and Bruch's membrane seen in CS animals by EM. <br><br>CONCLUSIONS: Taken together, these findings suggest that AP inhibitors not only prevent, but have the potential to accelerate the clearance of complement-mediated ocular injury. Improving our understanding of the regulation of the AP is paramount to developing novel treatment approaches for AMD.<p />  <p>Language: en</p>
LA  - en
SN  - 0146-0404
UR  - http://dx.doi.org/10.1167/iovs.15-18471
ID  - ref1
ER  -