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Discovery Opens Doors for AAV Gene Therapy Research

Adeno-associated virus vectors (AAV) are the most commonly used viral vectors for gene therapy. A new discovery of a ‘lock’ mechanism involved in how AAVs function properly may provide a missing piece of information that can help scientists better direct AAV gene transfers to specific organs.

Gene therapy, which is the transplantation of normal genes into cells in place of missing or defective ones in order to correct genetic disorders, first emerged as a field nearly 50 years ago. But, only recently have scientists made progress delivering genetic material to cells through what are called adeno-associated virus vectors (AAV). AAVs are the most commonly used viral vectors for gene therapy in living organisms.

AAVs are vectors—or delivery vehicles—that are created from a virus, which is made harmless by molecular engineering and serves to carry genetic material to a cell target. AAVs have shown promise in gene therapy and currently are being tested in clinical trials for diseases affecting the eye, muscles, and nervous system. Two AAV therapies are approved by the U.S. Food and Drug Administration for a form of blindness and neuromuscular disease.

Despite these advances and more AAVS in testing and treatment than ever before, how exactly this new class of medicine accomplishes gene transfer has remained poorly understood by the scientific community.

That is, until now.

Massachusetts Eye and Ear researchers have uncovered more information on the mechanism behind these AAV therapies. A team of scientists led by Luk Vandenberghe, PhD, director of the Grousbeck Gene Therapy Center, identified a protein receptor called GPR108. The team has shown it serves as a molecular ‘lock’ to the cells, which allows AAV vectors carrying the appropriate ‘key’ to gain access to the cells. GPR108 is required for most AAVs, including those used in the FDA-approved gene therapies, to gain access to cells and tissues that are the treatment’s target.

“For years we have known that AAV gene transfer is highly effective, but we have yet to learn how that is achieved and why some AAV types function differently than others,” said senior study author Dr. Vandenberghe. “This finding may enable scientists to better direct AAV gene transfers to targeted cell tissues in order to treat specific genetic diseases.”

The study recently published in Molecular Therapy.

Crossing the jungle gym of gene therapy

Despite the increase in the study of AAV therapies, scientists have been limited in their ability to create and test new treatments because the mechanism of actions involved with AAVs has been poorly understood.

Dr. Vandenberghe compares delivering AAV genetic therapies to a cell to crossing a ravine using monkey bars on a jungle gym. Each bar is a cellular factor that the AAV relies on to eventually make it into the nucleus of the cell. Last year, Stanford University researchers identified one important ‘crossbar’ in a highly conserved AAV entry receptor called AAVR. In this new study, the research team identified a second necessary cellular co-factor.

For the study, the researchers used a genome-wide CRISPR screening tool to look at 100,000 genes and determine which cells played a role in AAV targeting. They identified GPR108 as the entry factor that was required for access to all AAV variants tested except one. GPR108 was shown to be critical for most AAVs that are currently being studied clinically, including AAVs used in the two FDA-approved gene therapies.

Gaining cellular access is a critical step in delivering gene therapy. This discovery of GPR108 as a ‘lock’ for AAV may provide a crucial piece of information that can help scientists better explain, predict and direct AAV gene transfers to specific tissues, and ultimately develop more targeted therapies.

“This ‘lock’ discovery might enable us to better design these vectors for specific purposes,” said Dr. Vandenberghe.

Researchers look toward therapies for genetic eye diseases

Dr. Vandenberghe and his team will continue to study this mechanism and the biology of AAVs with the hope of optimizing these vectors for therapies. Their team is working on developing vectors that target specific genetic eye diseases, including retinitis pigmentosa and Usher syndrome.

“Gene-based therapies for eye diseases are a major focus of our research mission at Massachusetts Eye and Ear, where our goal is to end blindness. This latest work by Dr. Vandenberghe and colleagues is a major breakthrough in our understanding of viral vectors, and will guide further development of this promising class of AAV therapies,” said Joan W. Miller, MD, chief of Ophthalmology at Mass. Eye and Ear.

Funding for the study is supported by National Institutes of Health (NIH R01 AI130123), and Lonza Houston, and Giving Grousbeck Fazzalari.


Dr. Vandenberghe discloses a financial interest in TDTx, a company developing AAV gene therapies. He is an inventor of technology related to AAV gene therapy, a founder of the company, and also serves on its Board of Directors. He is the recipient of royalties on products incorporating these technologies including Zolgemsma™. Dr. Vandenberghe holds equity to Akouos, a hearing gene therapy company. He also serves a consultant to various biopharmaceutical entities in the field of gene therapy including Novartis, manufacturer of Luxturna(™) and Zolgensma™. Dr. Vandenberghe’s interests were reviewed and are managed by Mass. Eye and Ear and Partners HealthCare in accordance with their conflict of interest policies.

1 thought on “Discovery Opens Doors for AAV Gene Therapy Research”

  1. I am a 73 year old male whom has been diagnosed with RP. Genetic testing shows that I have a defective RP 1 gene from my mother. I am a participant in the My Retinal Tracker Registry. I live in Orlando Florida am retired and available for travel. I original traveled to Harvard in 1974 or 5, upon initial diagnosis from the Florida Eye Clinic in Altamonte Springs Florida where I presently treated by Dr. Xavior. Am interested in clinical trials.

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