Abstract
SummaryGene therapies using adeno-associated viruses (AAVs) are among the most promising strategies to treat or even cure hereditary and acquired retinal diseases. However, the development of new efficient AAV vectors is slow and costly, largely because of the lack of suitable non-clinical models. By faithfully recreating structure and function of human tissues, human induced pluripotent stem cell (iPSC)-derived retinal organoids could become an essential part of the test cascade addressing translational aspects. Organ-on-chip (OoC) technology further provides the capability to recapitulate microphysiological tissue environments as well as a precise control over structural and temporal parameters. By employing our recently developed retina on chip that merges organoid and OoC technology, we analyzed the efficacy, kinetics, and cell tropism of seven first- and second-generation AAV vectors. The presented data demonstrate the potential of iPSC-based OoC models as the next generation of screening platforms for future gene therapeutic studies.
Highlights
Retinal diseases are the most common cause of visual impairment in developed countries and have become the worldwide leading cause of childhood blindness (Gilbert and Foster, 2001)
AAV2, AAV2.7m8, and ShH10 show expression and cellular tropism after intravitreal application in mouse retina First, performance of generated recombinant associated viruses (AAVs) vectors was analyzed in the eyes of adult mice
Different doses of AAV2 harboring either linear single-stranded AAV2 or self-complementary AAV2 and AAV2.7m8 with self-complementary sequence of eGFP under the control of the cytomegalovirus (CMV) promotor were subjected to intravitreal application (Figure 1)
Summary
Retinal diseases are the most common cause of visual impairment in developed countries and have become the worldwide leading cause of childhood blindness (Gilbert and Foster, 2001). These conditions have enormous consequences on the quality of life for the affected patients. The absence of effective therapies resulting in poor prognosis creates a high emotional burden. Renewed efforts to find treatment options are constantly being undertaken. Despite being in the early stages, molecular diagnosis and new treatment strategies such as optogenetics, cell transplants, and gene therapy have already shown the first promising results. In 2017, the first gene therapy for Leber congenital amaurosis was approved by the US Food and Drug Administration (FDA) (Trapani and Auricchio, 2018)
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