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Dr. Jessica Morgan
By Rebecca Salowe

Scheie Vision Summer 2018

In December 2018, the Food and Drug Administration approved the first gene therapy for an inherited disease. This treatment delivers a corrected gene (RPE65) to the retina, restoring visual function in patients. This advancement received national attention, with articles published in Time, The Wall Street Journal, Washington Post, Los Angeles Times, and more.

Today, researchers at the Center for Advanced Retinal and Ocular Therapeutics (CAROT) are turning their attention to other retinal degenerations, seeking to expand the range of treatment options available to patients with hereditary blindness. Jessica I. W. Morgan, PhD, an Assistant Professor of Ophthalmology, has a unique and vital role in this process.

In many retinal diseases, vision loss is caused by damage to rod and cone photoreceptors. Thus, researchers must be able to closely evaluate the structure and function of photoreceptors in order to gauge if a treatment is effective. Did the therapy help to protect and preserve these cells? Is a disease worsening – or has its progression been halted? 

Dr. Morgan uses a technology called adaptive optics to answer these questions. Adaptive optics imaging provides high-resolution photos of individual photoreceptors, allowing her to evaluate how single cells are affected by treatments for retinal disease.

“Many advances are being made in regenerative medicine, gene therapy, stem cell therapy, and optogenetics – and all of those treatment approaches aim to restore function to individual cells,” she explained. “And we now have the capability to noninvasively observe individual photoreceptors. The question is: can we use that information to assess if a treatment is safe and providing a benefit to patients?”

Dr. Morgan believes that the answer will soon be yes, with a bit more work. Currently, adaptive optics imaging provides information solely on structural changes in photoreceptors; this information has not previously been correlated with functional changes in vision. Thus, Dr. Morgan’s current research focuses on understanding how the structural changes observed through adaptive optics imaging affect the function of those same photoreceptors.

In 2015, Dr. Morgan began collaborating with David Brainard, PhD, who had recently received a Stein Innovation Award from Research to Prevent Blindness. Together, they have incorporated two distinct methods of assessing photoreceptor function into the adaptive optics imaging system, with the goal of correlating this functional information with structural images. 

The first method, cellular-scale microperimetry, measures cone function by testing a patient’s response to a visual stimulus. The stimulus is focused on an individual cone, taking advantage of the high resolution provided by the adaptive optics system. “We flash a light that is received by one cone only and ask a patient, ‘Did you see it? Did you not?’” explained Dr. Morgan. Over multiple trials, Dr. Morgan can then determine the ‘threshold of seeing’ at the individual cone level.

The second method measures how the intrinsic reflectance of individual photoreceptors changes in response to light stimulation. Again, the stimulus is delivered through the adaptive optics system; cone response is then observed using infrared imaging light. Dr. Morgan tested this method on healthy controls, showing that intrinsic reflectance is an accurate reflector of actual cone function. These results were published in Biomedical Optics Express.

Now that these techniques have been successfully applied to healthy controls, the next step is turning to patients with retinal disease.

“We are now undertaking cross-sectional and longitudinal studies to compare functional responses from photoreceptors affected by retinal disease to those from normal controls,” said Dr. Morgan.  

These functional tests allow disease progression to be closely monitored in a way that was not previously feasible. Physicians will thus be able to provide a more precise diagnosis and prognosis to patients with retinal diseases.

“Ultimately, we want to use these methods to assess which photoreceptors in the retina take up a therapy and which ones do not,” said Dr. Morgan. “The cells could regain normal function, regain partial function, stay steady, decline, or decline faster.” This data provides valuable information on how many “treated cells” are needed to maintain good vision or improve vision. Or, in the event that a therapy fails, researchers can determine if a therapy should be amped-up to target more cells.

The first disease to be targeted is choroideremia, a rare retinal degeneration that causes gradual loss of vision in males. Phase I/II gene therapy clinical trials are currently in progress at CAROT. Dr. Morgan recently received a National Institutes of Health RO1 grant to conduct add-on studies to these trials.  

“We already know that cone photoreceptors remain structurally present in near normal numbers in patients with choroideremia,” explained Dr. Morgan. “However, our preliminary findings show that the functional response of these cells is reduced. Now we want to know whether gene therapy restores their function.”

As clinical trials for gene therapy and other cellular therapies grow more common, Dr. Morgan’s research on how these therapies alter photoreceptor structure and function will become more and more valuable. Her foresight in developing precise ways to evaluate disease outcomes may soon affect the diagnosis and treatment of many retinal diseases.

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