The Byrne Lab develops gene therapies for retinal disease. Inherited retinal dystrophies include a diverse group of blinding disorders that have a profound impact on the quality of life of patients. Approximately 1 in 3000 people worldwide are affected by inherited retinal degenerations. This group of diseases involve mutations in more than 200 genes, with autosomal recessive, dominant, X-linked, and complex patterns of inheritance. Most mutations that cause retinal degeneration are expressed in photoreceptors, the light sensitive cells of the retina, or RPE cells, which provide support to photoreceptors, and these mutations result in dysfunction and eventual death of photoreceptors, leading to a loss of vision.
There are currently no effective treatments for most forms of inherited retinal degeneration. However, gene therapy, in which a healthy copy of a mutated gene or a therapeutic protein is delivered to cells in the retina, is a highly promising approach to treating retinal disease. The most effective approach to deliver a therapeutic gene to the retina is using viruses, which have evolved over millions of years as highly efficient gene delivery systems. In viral vector-mediated gene therapy, the viral genome is replaced with a cassette containing a promoter driving expression of a therapeutic transgene. The virus is then injected into the eye, where it infects retinal cells, carrying its genetic payload to the nucleus, and resulting in expression of a therapeutic protein.
Before gene therapy strategies are effective, efficient and applicable to most retinal diseases, there are significant obstacles that must be overcome. These include developing gene therapy approaches for diseases involving large genes, dominant mutations, and mutations in non-coding regions. The Byrne lab uses bioengineering approaches, and high throughput, computationally guided methods, to create new gene therapies for retinal disease, including gene augmentation, genome editing and optogenetic strategies.
Bilge E. Ozturk, Molly E. Johnson, Michael Kleyman, Serhan Turunc, Jing He, Sara Jabalameli, Zhouhuan Xi, Meike Visel, Valerie L. Dufour, Simone Iwabe, Felipe Pompeo Marinho, Gustavo D. Aguirre, Jose-Alain Sahel, David V. Schaffer, Andreas R. Pfenning, John G. Flannery, William A. Beltran, William R. Stauffer, Leah C. Byrne. scAAVengr, a transcriptome-based pipeline for quantitative ranking of engineered AAVs with single-cell resolution. eLife. 2021;10:e64175 DOI: 10.7554/eLife.64175
Zhouhuan Xi, Bilge E. Ozturk, Molly E. Johnson, William R Stauffer, Leah C. Byrne. Quantitative single-cell transcriptome-based ranking of engineered AAVs in human retinal explants. bioRxiv. Sept 27 2021. https://doi.org/10.1101/2021.09.27.461256.
Gemayel M, Byrne LC, Ciulla T, Sahel JA. Delivery of Genetic Information: Viral Vector and Nonviral Vector Gene Therapies. Int Ophthalmol Clin. 2021 Jul 1;61(3):35-57. doi: 10.1097/IIO.0000000000000360.
Byrne LC, Day TP, Visel M, Fortuny C, Dalkara D, Merigan WH, Schaffer DV, Flannery JG. In vivo directed evolution of AAV in the primate retina. JCI Insight. 2020 Apr 9;. doi: 10.1172/jci.insight.135112. https://insight.jci.org/articles/view/135112.
Shen SQ, Myers CA, Hughes AE, Byrne LC, Flannery JG, Corbo JC. Massively parallel cis-regulatory analysis in the mammalian central nervous system. Genome Res. 2016 Feb;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 May 7;161(4):817-32.
Byrne LC, Lee T, Flannery JG, Dalkara D. The expression pattern of systemically injected AAV9 in the developing mouse retina is determined by age. Mol Ther. 2015 Feb;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 Jan;1 25(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 Jun;21(6):585-92.
Day TP/Byrne LC, Schaffer DV, Flannery JG. Advances in AAV Vector Development for Gene Therapy in the Retina. Adv Exp Med Biol. 2014;801:687-93.
Byrne LC, Khalid F, Lee T, Zin EA, Greenberg KP, Visel M, Schaffer DV, Flannery JG. AAV-mediated, optogenetic ablation of Müller Glia leads to structural and functional changes in the mouse retina. PLoS One. 2013 Sep 27;8(9):e76075.
Dalkara D/Byrne LC, Klimczak RR, Visel M, Yin L, Merigan WH, Flannery JG, Schaffer DV. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med. 2013 Jun 12;5(189):189ra76.
Dalkara D, Byrne LC, Lee T, Hoffmann NV, Schaffer DV, Flannery JG. Enhanced gene delivery to the retina through systemic administration of tyrosine mutated AAV9. Gene Ther. 2012 Feb;19(2):176-81.