Viruses, Gene Therapy, and Retinal Disease

Leah Byrne, PhD, assistant professor in the Department of Ophthalmology and assistant professor of bioengineering in the Swanson School of Engineering at the University of Pittsburgh, specializes in the study and application of gene-based approaches to treat inherited retinal dystrophies. Dr. Byrne’s research specifically investigates the use of viral vector-mediated methods in animal models to deliver gene therapies to the retina and to edit or alter the aspects of the genome responsible for inherited retinal diseases. Dr. Byrne’s viral vector research has largely focused on developing and testing novel adeno-associated viral (AAV) vectors for genetic therapy delivery.

Dr. Byrne is a neuroscientist by training. She completed her PhD in neuroscience at the University of California, Berkeley in 2011, followed by a postdoctoral fellowship as a Ruth L. Kirschstein NRSA Postdoctoral Fellow at the Helen Wills Neuroscience Institute at Berkeley and the School of Veterinary Medicine at the University of Pennsylvania.

As a postdoctoral researcher, Dr. Byrne engineered next-generation AAV viruses for retinal gene therapy, and she developed high-throughput methods for directed evolution of viral vectors. This research remains a focus of her work and that of the Gene Therapy for Retinal Disease Laboratory she directs at the University of Pittsburgh School of Medicine.

Using Viruses to Alter Retinal DNA

Inherited diseases of the retina affect roughly 2.5 million people worldwide or about 1 in 3,000. “There is a broad spectrum of inherited retinal disease, driven by an even broader spectrum of mutations in more than 200 genes. For the overwhelming majority of these retinal disorders, we have no treatments. These diseases will cause people to lose their vision. My research seeks to develop gene-modifying therapies and delivery methods that can prevent or correct disease after it occurs,” says Dr. Byrne.

Because viruses at a fundamental level infect host cells, transfer their DNA, and replicate themselves, harnessing the molecular power of what a virus does naturally may prove to be an effective means for altering defective or damaged genes or gene sequences responsible
for various inherited retinal disorders. Be it for retinal diseases, cancer, metabolic disorders, or brain disorders such as Parkinson’s disease, viral vector-mediated delivery of gene therapies is making progress, but significant obstacles still must be overcome.

As Dr. Byrne points out, these barriers to effective gene therapy delivery include overcoming diseases driven by large genes, those of a dominant inherited nature, and how to understand and overcome genetic mutations that drive diseases that occur in noncoding regions of the genome devoted to retinal development.

A possible technique for overcoming some of these barriers to effective treatment options is a process known as directed evolution. Dr. Byrne uses this technique that essentially can speed up the natural process of viral evolution but in a highly controlled manner in the laboratory. This technique can allow for more rapid creation of viral models to test in the lab. Dr. Byrne’s lab also is investigating the use of CRISPR/Cas9 technology to develop novel gene editing approaches to create new molecular targets and therapies that can reprogram aspects of the genome responsible for retinal disease.

Recent Awards, Grants, and Speaking Engagements

In 2017, Dr. Byrne served as an associate scientific advisor for the journal Science Translational Medicine, and she was named as an Emerging Vision Scientist by the National Alliance for Eye and Vision Research. Dr. Byrne also was a 2017 recipient of a Career Development Award from the Research to Prevent Blindness (RPB) organization. Dr. Byrne’s grant from RPB is for the “creation of a flexible method of gene and protein delivery in the retina through a modular system of small viruses.”

In April 2018, Dr. Byrne was invited to give a University of Pittsburgh Senior Vice Chancellor’s Research Seminar lecture. Dr. Byrne’s presentation dealt with viral vector-mediated gene delivery for
retinal disease. More recently Dr. Byrne was awarded an individual investigator grant from the Foundation Fighting Blindness. Her grant, “Designing Optimal Viral Gene-Delivery Systems for Retinal Diseases,” will continue to support her research to engineer viruses capable of delivering therapeutic genes to the retina. Dr. Byrne’s work seeks to create a group of viral promoters and capsids for each of the different cell types in the retina and make these tools available to other researchers in the field to spur on and speed up the search for curative therapies.
For Further Reading

Dr. Byrne’s recent publications include:

Gaj T, Ojala DS, Ekman FK, Byrne LC, Limsirichai P, Schaffer DV. In Vivo Genome Editing Improves Motor Function and Extends Survival in a Mouse Model of ALS. Sci Adv. 2017; 3(12): eaar3952.
Byrne LC. Anti-VEGF AAV2 Injections: The Fewer the Better. Sci Transl Med. 2017; 9(393). Pii: eaan4921.
Byrne LC. What’s Old Is New Again: Autologous Stem Cell Transplant for AMD. Sci Transl Med. 2017; 9(387).
Byrne LC. Rounding Up Sickle Cells With Gene Therapy. Sci Transl Med. 2017; 9(381). Pii: eaam9864.
Shen SQ, Myers CA, Hughes AE, Byrne LC, Flannery JG, Corbo JC. Massively Parallel Cis-Regulatory Analysis in the Mammalian Central Nervous System. Gen Res. 2016; 26(2): 238-55.
Aït-Ali N, Fridlich R, Millet-Puel G, Clérin E, Delalande F, Jaillard C, Blond F, Perrocheau L, Reichman S, Byrne LC, Olivier-Bandini A, Bellalou J, Moyse E, Bouillaud F, Nicol X, Dalkara D, van Dorsselaer A, Sahel JA, Léveillard T. Rod-derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis. Cell. 2015; 161(4): 817-32.
Xue Y, Shen SQ, Jui J, Rupp AC, Byrne LC, Hattar S, Flannery JG, Corbo JC, Kefalov VJ. CRALBP Supports the Mammalian Retinal Visual Cycle and Cone Vision. J Clin Invest. 2015; 125(2): 727-38.
Byrne LC, Lin YJ, Lee T, Schaffer DV, Flannery JG. The Expression Pattern of Systemically Injected AAV9 in the Developing Mouse Retina Is Determined by Age. Mol Ther. 2015; 23(2): 290-6.
Byrne LC, Dalkara D, Luna G, Fisher SK, Clérin E, Sahel JA, Léveillard T, Flannery JG. Viral-mediated RdCVF and RdCVFL Expression Protects Cone and Rod Photoreceptors in Retinal Degeneration. J Clin Invest. 2015; 125(1): 105-16.
Byrne LC, Oztürk BE, Lee T, Fortuny C, Visel M, Dalkara D, Schaffer DV, Flannery JG. Retinoschisin Gene Therapy in Photoreceptors, Müller Glia or All Retinal Cells in the Rs1h-/- Mouse. Gene Ther. 2014; 21(6): 585-92.