期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：47
DOI：10.1073/pnas.2107444118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Many blinding diseases afflict photoreceptors, specialized cells in the retina that capture and transduce light to initiate vision. Biomarkers that are sensitive to photoreceptor health are crucial for early detection and effective treatment monitoring of these diseases yet remain elusive. Here, we develop an optical biomarker, based on optoretinographic photoreceptor responses to light stimulation, that reflects the degree of dysfunction of individual cone photoreceptors in patients with retinitis pigmentosa (RP), the most common inherited retinal degenerative disease. Our results show that this biomarker may be beneficial for assessing the functionality of remaining retinal cells in RP patients and for assessing efficacy of treatments such as gene therapy and stem cell transplantation for RP and other diseases afflicting photoreceptors.
Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerative diseases, whose most debilitating phase is cone photoreceptor death. Perimetric and electroretinographic methods are the gold standards for diagnosing and monitoring RP and assessing cone function. However, these methods lack the spatial resolution and sensitivity to assess disease progression at the level of individual photoreceptor cells, where the disease originates and whose degradation causes vision loss. High-resolution retinal imaging methods permit visualization of human cone cells in vivo but have only recently achieved sufficient sensitivity to observe their function as manifested in the cone optoretinogram. By imaging with phase-sensitive adaptive optics optical coherence tomography, we identify a biomarker in the cone optoretinogram that characterizes individual cone dysfunction by stimulating cone cells with flashes of light and measuring nanometer-scale changes in their outer segments. We find that cone optoretinographic responses decrease with increasing RP severity and that even in areas where cone density appears normal, cones can respond differently than those in controls. Unexpectedly, in the most severely diseased patches examined, we find isolated cones that respond normally. Short-wavelength–sensitive cones are found to be more vulnerable to RP than medium- and long-wavelength–sensitive cones. We find that decreases in cone response and cone outer-segment length arise earlier in RP than changes in cone density but that decreases in response and length are not necessarily correlated within single cones.
