Researchers based at the Stanford University School of Medicine and the Oregon Health & Science University have reported the identity of a key receptor critical to the delivery of AAV gene therapy payloads. Despite the considerable number of AAV gene therapy clinical trials underway worldwide, the specific mechanism through which AAV vectors deliver their engineered genes to target cells has been poorly understood. With over 30 gene therapy trials underway in ophthalmology alone, the finding may have the potential to improve delivery efficiencies to a wide number of tissue targets and, in time, may expand the population of cells previously refractive to AAV gene delivery.
The researchers used an unbiased genome-wide screening strategy based on insertional mutagenesis of a haploid human cell library to uncover and enrich for cells that could be shown to be significantly affected by mutations in certain genes. A previously poorly characterized gene coding for a transmembrane protein was identified from the screen, KIAA0319L, and was subsequently denoted as “AAVR” – adeno-associated virus receptor. In the study, published in the journal Nature, the research team showed that elimination of AAVR from eight distinct human and mouse cell lines resulted in the cells becoming highly resistant to AAV infection. Conversely, over-expression of AAVR in previously refractive cell lines significantly increased their susceptibility to AAV. The researchers went on to show that AAVR knockouts were also resistant to infection by a wide range of AAV serotypes including serotypes 1, 2, 3B, 5, 6, 8 and 9. The AAVR gene product did not appear to have a well-documented functionality in the available literature however, one study postulated a link to dyslexia and to a potential role in neuronal migration.
The findings have implications beyond the basic biology of AAV infection in that manipulation of the newly discovered receptor may provide significant clinical application in the development of gene therapy treatments across a range of disorders, not least of all in the field of ophthalmology and retinal disease. A number of research groups worldwide, including approximately 40 commercial entities such as Spark Therapeutics, AGCT, Avalanche, NightStaRx and GenSight, all run very active clinical programs using AAV gene therapy. To date, current clinical programs include testing potential gene therapy treatments for Leber’s congenital amaurosis, retinitis pigmentosa, Leber’s hereditary optic neuropathy, choroideremia, wet and dry AMD, achromatopsia, X-linked retinoschisis and several other debilitating ocular disorders which are presently in the pipeline planning stages.