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Dr. Manzar Ashtari performing an MRI
Dr. Ashtari performing an MRI on a study participant.
By Alexandra Brodin

Scheie Vision Summer 2020

 

Manzar Ashtari, PhD, is the Principal Investigator of a five-year study titled “Plasticity of the Human Visual System Studied in Response to Retinal Gene Therapy.” Beginning in 2016, the goal of this grant is to investigate what happens in the brain’s visual system after patients undergo retinal gene therapy, a groundbreaking procedure to improve visual function in patients with inherited ocular disease.

 

Dr. Ashtari is an Associate Professor of Ophthalmology and Radiology at the University of Pennsylvania (UPenn). She is the Director of the Central Nervous System (CNS) Imaging Laboratory at the Center for Advanced Retinal and Ocular Therapeutics (CAROT). Dr. Ashtari’s research is funded by an R01 grant from the National Eye Institute and has resulted in high-impact publications in journals such as Science: Translational Medicine, Ophthalmology, and The Lancet.

 

In 2017, retinal gene therapy became the first FDA-approved gene therapy for an inherited disease in the United States. The research to develop this therapy, known commercially as Luxturna, was spearheaded by Scheie investigators Jean Bennett, MD, PhD, the F.M. Kirby Professor of Ophthalmology and Director of CAROT, and Albert Maguire, MD, Professor of Ophthalmology. Luxturna has been found safe and effective for restoring vision to patients with Leber’s congenital amaurosis (LCA), a severe retinal degenerative disease caused by mutations in the RPE65 gene. Dr. Ashtari’s grant builds on the development of retinal gene therapy, and this work would not be possible without the support of Dr. Bennett.

 

Although retinal gene therapy involves an injection in the eye, Dr. Ashtari hypothesized that the procedure would impact the brain as well. “Gene therapy doesn’t just affect the retina—it also remodels the brain,” she said. Dr. Ashtari and her team used non-invasive neuroimaging methods, including functional MRI (fMRI), diffusion tensor MRI (dMRI), and resting state fMRI (rsfMRI), to study this remodeling. Participants in the study were evaluated at baseline and again at one, three, and six months after retinal gene therapy. Evaluations then continued annually for five years following the procedure, and a randomized control group was evaluated prior to receiving retinal gene therapy. The CNS lab participated in the three phases of the LCA2 clinical trials, which took place at The Children’s Hospital of Philadelphia and UPenn.

 

As Dr. Ashtari predicted, vision restoration due to retinal gene therapy led to structural and functional changes within the visual cortex. Following the procedure, the primary visual pathways associated with the treated retina significantly improved, resembling the pathways observed in sighted control subjects. In contrast, the primary visual pathways associated with the untreated retina continued to degenerate.

 

These findings demonstrate the incredible plasticity of the brain and open possibilities for utilizing the connections between the retina and the brain to improve patient outcomes. “My hope with my grant is to build a bridge between the retina and the brain,” Dr. Ashtari expressed. “Your retina could be just perfect, but if something is wrong with your brain, you can’t see. Unfortunately, this connection often gets neglected.”

 

The term plasticity refers to the brain’s ability to adapt to experiences and is often associated with functional changes. Much of our current understanding of brain plasticity comes from animal studies. Dr. Ashtari’s lab is the first to study human brain plasticity in the event of vision restoration.

 

One important example of brain plasticity occurs when, in the case of blindness or low vision, areas of the brain that support vision can give up neural “real estate” to functions associated with other senses, like smell, touch, or hearing. This phenomenon, known as cross-modal plasticity, often causes people who lose their vision to experience enhancement of their other senses.

 

It has been suggested that if cross-modal plasticity occurs, the visual pathways will be unable to respond when visual input does become available. However, Dr. Ashtari’s results show that this idea underestimates the plasticity of the brain. Even in cases of prolonged visual deprivation (over 40 years), the treated retina and related visual pathways are significantly more responsive to light stimulation when compared to the untreated retina.

 

Dr. Ashtari also found that the visual real estate given up to other sensory functions will continue to participate in those other functions, even after they once again begin to support vision. “People in the field have published that if you have cross-modal plasticity, then vision is not going to be as effective,” Dr. Ashtari said. “But we have found that the neurons of the visual cortex are multitasking neurons.” In other words, neurons in the visual cortex can potentially be involved in processing multiple sensory functions, with little detriment to vision.

 

Dr. Ashtari is working to better understand the visual pathways created in the brains of these patients. It is crucial to characterize how these visual pathways form and change in response to retinal gene therapy in order to maximize visual outcomes in this patient population. “The results are fantastic,” Dr. Ashtari said about retinal gene therapy. “But we may still be able to make it better.”

 

One way to maximize the benefits of retinal gene therapy may be to prescribe rehabilitation to patients who undergo this procedure. Dr. Ashtari’s research suggests that a critical window opens up after retinal gene therapy. This critical window is defined by a peak in the dendritic population within the visual cortex, which occurs about 2-3 months after the procedure.

 

Dendrites are the parts of a neuron that allow it to connect to other neurons, forming neural pathways. An increase in dendrites corresponds to an increased capacity for forming and strengthening these pathways.

 

Dr. Ashtari’s research shows rehabilitation or physical therapy may allow patients to take full advantage of this peak in the dendritic population. “We could maximize these connections if we would have some sort of rehabilitation for the patients after retinal gene therapy,” Dr. Ashtari explained. “I think our data show that, just like when doctors do hip or knee replacements and send patients to physical therapy, we should be doing something similar with our gene therapy patients.”

 

One form that this rehabilitation could take in the future involves virtual reality (VR) technology. Patients could wear VR goggles and play games designed to stimulate the neurons in the visual cortex in ways that properly exercise that area of the brain, thus encouraging neural connections to develop. “We need to strengthen the ‘hand-shaking’ between the retina and the brain,” Dr. Ashtari said.

 

In the final year of her R01, Dr. Ashtari and her team will continue their efforts in exploring the underlying mechanisms for brain plasticity and mapping the dynamic changes that the brain undergoes to improve vision after retinal gene therapy.

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