Karen Jeng-Miller, MD, MPH
Mass Eye & Ear
This year, the 2018 Charles L. Schepens Lectureship was awarded to Dr. Paul Sternberg, G.W. Hale Professor and Chair of Vanderbilt Eye Institute, and past president of the American Academy of Ophthalmology.
Dr. Emily Chew began with an introduction to Dr. Sternberg, starting with his time at Wilmer (highlighting his musical theater skills!), to his lifelong dedication as an academician, researcher, and leader in the vitreoretinal field, and ending with his devotion as a family man to his wife and children, and friend and colleague to all members of the medical community.
As Dr. Sternberg began to speak, he framed his lecture around the following main theme: How do we help the large number of patients who aren’t responding to treatments that we have developed? Up to fifty percent of blindness in the United States continues to be attributed to age-related macular degeneration. Due to limited protective treatments in many neuro-degenerative conditions (AREDS in AMD, IOP lowering therapies in glaucoma), vision loss occurs in many cases. Unfortunately, this serves as a major medical problem with large social and economic burdens. As a result, Dr. Sternberg’s lectureship highlighted the role of regenerative medicine in addressing these needs:
- Why regenerative vision and what are the challenges?
- Where do we stand in current clinical care?
- What approaches should we consider?
- How will regenerative medicine transform eye care?
Dr. Sternberg begins to answer these questions with the promises of gene therapy. He begins by discussing applications of viral-mediated gene therapy, which led to the breakthrough therapeutic, Luxterna, the first FDA-approved gene therapy for any condition in the body. There are also many ongoing research and trials to explore the potential of gene therapy, such as viral-mediated gene delivery of modified erythropoietin for treatment of optic nerve degeneration in glaucoma or viral-mediated gene delivery via intravitreal injection for Leber’s hereditary optic neuropathy.
However, Dr. Sternberg proposes that to broaden these approaches to a wider range of diseases of the central nervous system, it is important to turn to approaches via regenerative medicine. Regenerative medicine includes protection of vulnerable tissue prior to loss of function, repairing stressed or damaged neural tissue to help regain function, and restoring lost retina or nerve tissue to regain connectivity with the brain and vision.
A recent example of repair using gene therapy techniques was produced by Lim, et. al., published in 2016 in Nature Neuroscience, in which they increased mTOR activity via viral-mediated gene therapy to help repair degenerating axons in the optic nerve and improve visual performance. Data like this demonstrates that neural tissue has an innate ability and desire to survive and regenerate – but how do we stimulate this ability? This innate ability for regeneration has been particularly demonstrated in zebrafish models. In these models, Mueller cells have some intrinsic capacity to become stem-cell like in injury and transform themselves into photoreceptors and repopulate areas of damage in the retina (Wan et. al., Current Opinion in Genetics and Development, 2016).
Now, the important question is, how do we induce this regenerative state in mammalian retina? Only recently has this been demonstrated at Yale through a study by Yao, et. al. (Nature, 2018) in which a double knockout mouse (blocking key elements of the retinal phototransduction cascade) was treated with a two-step adeno-associated virus based reprogramming method to generate rod photoreceptors. This induced Mueller glial cells to proliferate and then assume a rod phenotype, thus increasing the number of rod photoreceptors. Functionally, this translated into increased ganglion cell activity and improved visual evoked potentials in the brain! Finally, ongoing work at Vanderbilt demonstrates that knockout of the p27Kip1 gene in Mueller cells can promote a pluripotent state with regenerative capacity.
In conclusion, Dr. Sternberg provides an optimistic outlook for regenerative visual neuroscience; that we will be able to develop novel mechanisms to avoid degeneration, activate intrinsic repair mechanisms in cases of neural damage, and restore function through transformation of intrinsic cells for replacement of damaged or absent tissue. Importantly, Dr. Sternberg cites the importance of mentorship and collaboration in order to accomplish these goals. Congratulations, Dr. Sternberg, on your Retina Research Award of Merit. We all look forward to the amazing contributions you will continue to make in the field of retina.