Advances towards personalized therapies for Stargardt disease

ABSTRACTIntroduction ABCA4-associated Stargardt disease (STGD1) leads to bilateral central vision loss and is responsible for 12% of inherited retinal disease-related blindness.The lack of approved treatments highlights the urgent need for effective therapies.Areas covered This review explores personalized treatments for STGD1, focusing on therapeutic alternative splicing, genome editing, and translational read-through technologies. Literature searches as of July 2023 were undertaken via PubMed.Expert opinion Significant progress has been made in sequencing technology revealing the complexities of theABCA4 locus. Comprehensive functional assays now enable the determination of pathogenicity for ABCA4variants of uncertain significance. These breakthroughs facilitate the application of gene expression modulation technologies, ushering in a new era of personalized therapeutics. By targeting the ABCA4 gene and manipulating its expression, tailored treatments can address ABCA4-associated STGD1, offering enhanced efficacy and precise interventions based on the individual’s genetic profile. These advancements provide hope to those affected by STGD1, with improved treatment options and the potential to prevent vision loss. The convergence of genetic analysis breakthroughs and gene expression modulation technologies revolutionizes our understanding and treatment of inherited disorders, unlocking a promising frontier in personalized therapeutics. This transformative approach to STGD1 holds promise for similar breakthroughs in other inherited conditions.KEYWORDS: ABCA4inherited retinal diseasejuvenile macular dystrophypersonalized therapeuticsantisense oligonucleotidestherapeutic alternative splicinggene editingCRISPRbase editorprime editingDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsAutosomal recessive Stargardt disease (STGD1) is a common monogenic inherited retinal dystrophy that leads to bilateral central vision loss and is responsible for 12% of IRD-related blindness.The spectrum of retinopathy associated with STGD1 includes childhood-onset cone-rod dystrophy, late-onset STGD1 with foveal sparing, and rapid-onset chorioretinopathy phenotype.STGD1 is caused by bi-allelic variants in the ATP-binding cassette transporter subfamily A4 gene (ABCA4) gene, which encodes the ABCA4 protein responsible for importing specific retinoid compounds in photoreceptor cells.Variable accumulation of cytotoxic lipofuscin-related fluorophores, such as A2E, is determined by combined deleterious effect of the biallelic ABCA4 variants and contributes to phenotypic variation.Antisense oligonucleotide (AONs) technology is being used to modify gene expression by targeting specific sequences and correcting splicing defects caused by ABCA4 variants, with particular observed in addressing pseudoexon inclusion resulting from by deep-intronic variants and exon elongation/skipping resulting from near-exon variants.Base editing and prime editing hold promise for addressing missense variants in the ABCA4 gene and could potentially target a significant proportion of ABCA4 variants associated with STGD1.Translational readthrough-inducing drugs (TRIDs) are being explored as a therapeutic strategy for STGD1 caused by nonsense variants, which account for approximately 12% of genetic diseases.Declaration of interestF.K. Chen and S. McLenachan are listed as co-inventor and co-contributor (respectively) on the international patent WO/2020/237294 (filed on 25 May 2020) for an antisense oligonucleotide drug treatment for retinitis pigmentosa. F.K. Chen is a consultant for PYC Therapeutics, Apellis and Janssen.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresA reviewer on this manuscript has disclosed that they are a consultant for Novartis and Janssen, unrelated to this manuscript. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Additional informationFundingThis paper was funded by the Channel 7 Telethon Trust; the Future Health Research and Innovation Fund; the Macular Disease Foundation Australia; the National Health & Medical Research Council of Australia, grants: GNT1116360, GNT1188694, GNT1054712, RF1142962; Retina Australia; and the McCusker Charitable Foundation.