Mol ther: study reveals the mechanism of AAV vector entering cells in gene therapy

January 26, 2020 / bioun / -- recently, researchers have identified an adeno-associated virus vector (AAV), a new cell entry factor of the most commonly used virus vector for gene therapy in vivo, and have shown the hope of transferring genetic therapy to affected tissues The researchers found that gpr108 is a G-protein-coupled receptor that acts as a molecular "lock" of cells Most AAVS, including those used in approved gene therapy, require gpr108 to enter cells Since activation of cell pathways is a key step in gene therapy, this finding may help scientists better explain, predict and ultimately transfer AAV genes to specific tissues (image source: www Pixabay Com) the study was recently published in the journal molecular therapy "Over the years, we have known that AAV gene transfer is very effective, but we have not yet understood how to achieve this transfer and why some types of AAV function differently than others," said Dr Luk Vandenberghe, associate professor of Ophthalmology at Grousbeck gene therapy center, Harvard Medical School "We have identified the cell's molecular 'lock', allowing AAV vectors carrying the appropriate 'key' to enter the cell This discovery may enable scientists to better transfer AAV gene to target cell tissues, so as to treat specific genetic diseases " For diseases affecting eyes, muscles and neurons, a variety of AAV are in clinical trials Luxturna and zolgensma, recently approved by the U.S Food and drug administration, are AAV gene therapy products for blindness and neuromuscular diseases However, the exact mechanism of gene transfer by this new drug is still poorly understood Gene therapy first appeared about 50 years ago, but only in the last decade have scientists made progress in delivering genetic material to target cells through AAV Despite recent advances in AAV research, scientists have been limited in creating and testing other therapies because the mechanism of action is not clear A few years ago, researchers at Stanford University found an important cross marker in the highly conservative AAV Dr Vandenberghe said: "our new research has found a second necessary cytokine that may allow us to better design these vectors for specific purposes." In the current study, researchers used genome-wide CRISPR screening tools to study 100000 genes and determine which cells play a role in AAV targeting They identified gpr108 as a highly conserved receptor recognition factor that is necessary for all AAV subtypes to enter the cell, except for the highly variable subtype AAV5 Gpr108 has proven to be critical for most of the AAVS currently under clinical study, including those used in two FDA approved gene therapies Dr Amanda M Dudek, lead author of the study, said the findings provide a further understanding of the mechanism to help explain and predict how AAV gene therapy targets tissues and cells "Our study reveals the mechanism of gpr108 in AAV entry," Dudek said With this knowledge, scientists can further deepen their understanding of AAV gene therapy safety, gene targeting and other characteristics of this new drug " Information source: researchers uncover mechanism for how common gene therapy vectors enter cells original source: Amanda M Dudek et al, gpr108 is a highly maintained AAV entry factor, molecular therapy (2019) Doi: 10.1016/j.ymthe.2019.11.005