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Boston, MA, Researchers at Massachusetts Eye and Ear and Schepens Eye Research Institute have reconstructed an ancient virus that is highly effective at delivering gene therapies to the liver, muscle, and retina. This discovery, published July 30 in Cell Reports, could potentially be used to design gene therapies that are not only safer and more potent than therapies currently available, but may also help a greater number of patients.
“We believe our findings will teach us how complex biological structures, such as AAVs (adeno-associated viruses), are built,” said senior study author Luk H. Vandenberghe, of Mass. Eye and Ear and Harvard Medical School Department of Ophthalmology. “From this knowledge, we hope to design next-generation viruses for use as vectors in gene therapy.”
Given its basic nature, a virus can be an ideal delivery system for gene therapy. In order to survive, a virus must infiltrate a host organism undetected and transfer its genetic material into the host’s cells, where it will use the host to replicate and proliferate. Taking advantage of this, researchers can insert therapeutic genes into a virus, then use the viruses to shuttle the genes to the appropriate cells or tissues inside a human body.
So far, AAVs used for gene therapy have been chosen from viruses that naturally circulate throughout the human population. If patients have been exposed to the virus, their bodies will likely recognize the virus, mount an attack, and destroy it before it can deliver the therapy. Engineering new, benign viruses could render the viruses unrecognizable and increase the number of people for whom a given gene therapy will work.
However, efforts to engineer improved AAVs have been stymied by the intricate structure of these viruses. Like pieces of a jigsaw puzzle, every protein in the shell of the virus must fit together perfectly for the virus to function normally. Altering proteins in one part of the virus to achieve a certain benefit, such as more efficient gene transfer or reduced recognition by host immune cells, could end up destroying the structural integrity of the entire shell.
To overcome this challenge, Vandenberghe and his colleagues at Harvard Medical School, Schepens Eye Research Institute, and Mass. Eye and Ear have turned to evolutionary history for guidance. Over time, AAV ancestors have undergone a series of changes that kept the structural integrity of the virus while slightly altering some of its functions. The researchers were able recreate an evolutionary timeline of the changes and build in the laboratory nine synthetic ancestors viruses. When injected into mice, the most ancient, Anc80 successfully targeted the liver, muscle, and retina, without producing toxic side effects.
In future studies, the researchers will characterize the interplay between the virus and host throughout evolution and continue to seek improved vectors for clinical applications. They will also examine the potential of Anc80 for treating liver diseases and retinal forms of blindness. “The vectors developed and characterized in this study demonstrate unique and potent biology that justify their consideration for gene therapy applications,” Vandenberghe says.
About Massachusetts Eye and Ear
Mass. Eye and Ear clinicians and scientists are driven by a mission to find cures for blindness, deafness and diseases of the head and neck. Now united with Schepens Eye Research Institute, Mass. Eye and Ear is the world's largest vision and hearing research center, developing new treatments and cures through discovery and innovation. Mass. Eye and Ear is a Harvard Medical School teaching hospital and trains future medical leaders in ophthalmology and otolaryngology, through residency as well as clinical and research fellowships. Internationally acclaimed since its founding in 1824, Mass. Eye and Ear employs full-time, board-certified physicians who offer high-quality and affordable specialty care that ranges from the routine to the very complex. U.S. News & World Report’s “Best Hospitals Survey” has consistently ranked the Mass. Eye and Ear Departments of Otolaryngology and Ophthalmology as top five in the nation. For more information about life-changing care and research, or to learn how you can help, please visit MassEyeAndEar.org.
About Harvard Medical School Department of Ophthalmology
The Harvard Medical School (HMS) Department of Ophthalmology is one of the leading and largest academic departments of ophthalmology in the nation. More than 350 full-time faculty and trainees work at nine HMS affiliate institutions, including Massachusetts Eye and Ear/Schepens Eye Research Institute, Massachusetts General Hospital, Brigham and Women’s Hospital, Boston Children’s Hospital, Beth Israel Deaconess Medical Center, Joslin Diabetes Center/Beetham Eye Institute, Veterans Affairs Boston Healthcare System, VA Maine Healthcare System, and Cambridge Health Alliance. Formally established in 1871, the department has been built upon a strong and rich foundation in medical education, research, and clinical care. Through the years, faculty and alumni have profoundly influenced ophthalmic science, medicine, and literature—helping to transform the field of ophthalmology from a branch of surgery into an independent medical specialty at the forefront of science.
This work was supported by the Harvard Medical School Department of Ophthalmology, Mass Eye and Ear, the Grousbeck Family Foundation, the Candyce Henwood Fund, the NIH Common Fund, Research to Prevent Blindness, and Foundation Fighting Blindness. Luk H. Vandenberghe (LHV) and Eric Zinn are inventors on a patent describing some of the methods and reagents described here. LHV is inventor on several patents on gene therapy technologies. LHV is co-founder, shareholder, member of the Scientific Advisory Board, and consultant of GenSight Biologics, an ophthalmology gene therapy company.
Cell Reports, Zinn et al. “In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector”
Cell Reports, published by Cell Press, is a weekly open-access journal that publishes high-quality papers across the entire life sciences spectrum. The journal features reports, articles, and resources that provide new biological insights, are thought-provoking, and/or are examples of cutting-edge research. For more information, please visit http://www.cell.com/cell-reports. To receive media alerts for Cell Reports or other Cell Press journals, firstname.lastname@example.org.
Image courtesy of Eric Zinn.