Retinal prosthesis systems have undergone significant advances in the past quarter century, resulting in the development of several different novel surgical and engineering approaches. Encouraging results have demonstrated partial visual restoration, with improvement in both coarse objective function and performance of everyday tasks. To date, four systems have received marketing approval for use in Europe or the United States, with numerous others undergoing preclinical and clinical evaluation, reflecting the established safety profile of these devices for chronic implantation. This progress represents the first notion that the field of visual restorative medicine could offer blind patients a hope of real and measurable benefit. However, there are numerous complex engineering and biophysical obstacles still to be overcome, to reconcile the gap that remains between artificial and natural vision. Current developments in the form of enhanced image processing algorithms and data transfer approaches, combined with emerging nanofabrication and conductive polymerization techniques, herald an exciting and innovative future for retinal prosthetics. This review provides an update of retinal prosthetic systems currently undergoing development and clinical trials while also addressing future challenges in the field, such as the assessment of functional outcomes in ultra-low vision and strategies for tackling existing hardware and software constraints.
Stargardt disease is a progressive retinal disorder caused by biallelic mutations in the ABCA4 gene that encodes the ATPbinding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease.
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