Columbia University Receives NIH Grant for Measures of Human Receptor and post Receptor Activity
Columbia University Receives a 2019 NIH Grant for $636,552 for Measures of Human Receptor and post Receptor Activity. The principal investigator is Donald Hood. Below is a summary of the proposed work.
Our long-term objective has been to develop noninvasive techniques for studying the human retina for both basic science and clinical purposes. By applying current theories of phototransduction to the full-field electroretinogram (ERG), we successfully developed widely used techniques for studying the global activity of the rod and cone receptors, as well as the rod bipolar cells. These indices of objective retinal function are appropriate outcome measures for treatment trials with systemically administered agents. However, many ongoing and anticipated clinical trials involving diseases of the photoreceptors require localized measures of retinal function, such as the multifocal electroretinogram (mfERG), static automated perimetry (SAP), and rod and cone-mediated fundus tracking perimetry, for evaluating treatment efficacy. With recent developments in retinal imaging, we can relate localized measures of visual function to the underlying structure. We have focused on frequency domain optical coherence tomography (fdOCT) and fundus autofluorescence (FAF). This work, supported by the current grant, has benefitted from our novel quantitative approaches for relating the thickness of retinal layers seen on fdOCT to other structural and functional measures. The upcoming focus will be on patients having Inherited Retinal Degenerations (IRDs), including STGD1, with identified genetic mutations. A primary goal is to provide insights into the pathophysiology and rates of progression in molecularly characterized patients with our novel imaging and functional measures. Present outcome measures in RP (primarily SAP and ERGs), and STGD1 (primarily visual acuity and FAF) are incapable of assessing change with modest sample sizes over a relatively short time interval, resulting in expensive and lengthy clinical trials. Our recent work with en face slab OCT represents a radical change in translational research in RP and STGD1. Our work in RP is virtually unique in the steps we are taking to establish quantitative OCT as a viable clinical trial outcome measure. As evidenced at the NEI-FDA endpoints workshop (NIH, Nov 9, 2016), there is considerable enthusiasm for an “anatomical” endpoint for IRDs. Nevertheless, there is still much to be done to expand the measures to EZ area and to establish the relationship between outer retinal structural alterations (i.e. EZ area) and functional loss. Planned experiments will determine the extent, nature and progression of receptor loss by developing and evaluating novel en face slab methods for quantifying the receptor regions on wide-field OCT scans, relating OCT parameters to rod and cone SAP, developing models relating rod and cone sensitivity to quantitative measures of inner and outer segment length, outer nuclear layer thickness, and inner nuclear layer thickness, and using multimodal imaging methods including OCT, infrared (IR) reflectance and FAF to test hypotheses about disease mechanisms and models of disease progression. Note that these experiments apply equally to RP and to STGD1. Taken together, these studies continue to support novel and more efficient outcome measures for clinical trials.