{"id":"doi:10.1038/s41434-022-00381-y","kind":"article","title":"Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease","authors":["Jeyakumar JM","Kia A","Tam LCS","McIntosh J","Spiewak J","Mills K","Heywood W","Chisari E","Castaldo N","Verhoef D","Hosseini P","Kalcheva P","Cocita C","Miranda CJ","Canavese M","Khinder J","Rosales C","Hughes D","Sheridan R","Corbau R","Nathwani A"],"author_count":21,"year":2023,"published":"2023-01-11","venue":"Gene therapy","cited_by":36,"doi":"10.1038/s41434-022-00381-y","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41434-022-00381-y","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41434-022-00381-y","updated":null,"pmid":"36631545","pmcid":"PMC10284695","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10284695/pdf","abstract":"Fabry disease is an X-linked lysosomal storage disorder caused by loss of alpha-galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of glycosphingolipids in multiple cells and tissues. FLT190, an investigational gene therapy, is currently being evaluated in a Phase 1/2 clinical trial in patients with Fabry disease (NCT04040049). FLT190 consists of a potent, synthetic capsid (AAVS3) containing an expression cassette with a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (AAV2/S3-FRE1-GLAco). For mouse studies FLT190 genome was pseudotyped with AAV8 for efficient transduction. Preclinical studies in a murine model of Fabry disease (Gla-deficient mice), and non-human primates (NHPs) showed dose-dependent increases in plasma α-Gal A with steady-state observed 2 weeks following a single intravenous dose. In Fabry mice, AAV8-FLT190 treatment resulted in clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in plasma, urine, kidney, and heart; electron microscopy analyses confirmed reductions in storage inclusion bodies in kidney and heart. In NHPs, α-Gal A expression was consistent with the levels of hGLA mRNA in liver, and no FLT190-related toxicities or adverse events were observed. Taken together, these studies demonstrate preclinical proof-of-concept of liver-directed gene therapy with FLT190 for the treatment of Fabry disease.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Preclinical evaluation of FLT190, a liver-directed AAV gene therapy for Fabry disease\" by Jeyakumar JM, Kia A, Tam LCS et al., https://doi.org/10.1038/s41434-022-00381-y, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-cell-therapy","name":"Gene & Cell Therapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}