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FLT201, a novel liver-directed AAV gene therapy candidate for Gaucher disease type 1

2025-08Journal article Open access
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dc.contributor.authorComper, Fabrizio
dc.contributor.authorMiranda, Carlos J.
dc.contributor.authorLiou, Benjamin
dc.contributor.authorDodev, Tihomir
dc.contributor.authorJeyakumar, Jey M.
dc.contributor.authorCanavese, Miriam
dc.contributor.authorCocita, Clement
dc.contributor.authorKhoshrou, Khashayar
dc.contributor.authorTiscornia, Gustavo
dc.contributor.authorChisari, Elisa
dc.contributor.authorStotter, Emmaline
dc.contributor.authorShehu, Erald
dc.contributor.authorSridharan,
dc.contributor.authorYu, I-Mei
dc.contributor.authorPandya, Jalpa
dc.contributor.authorKhinder, Jalpa
dc.contributor.authorNorthcott, Natalie
dc.contributor.authorKalcheva, Petya
dc.contributor.authorCorreia, Samantha
dc.contributor.authorSun, Ying
dc.contributor.authorDane, Allison P.
dc.contributor.authorSheridan, Rose
dc.contributor.authorNathwani, Amit C.
dc.contributor.authorCorbau, Romuald
dc.date.accessioned2025-09-29T12:13:23Z
dc.date.available2025-09-29T12:13:23Z
dc.date.issued2025-08
dc.description.abstractGaucher disease type 1 (GD1) is caused by mutations in the GBA1 gene, which result in deficient enzyme beta-glucocerebrosidase (GCase) activity and production with the harmful accumulation of the lipid substrate glucocerebroside. Replacement of GCase is current standard of care for GD1; however, GCase has a relatively short active half-life at both physiological and lysosomal pH and biweekly intravenous administration does not provide a consistent exposure to active enzyme. FLT201 is the first adeno-associated virus (AAV) gene therapy in clinical trials for treatment of GD1. FLT201 consists of a rationally designed AAV capsid (AAVS3) containing an expression cassette with an engineered GBA1 transgene that encodes a unique glucocerebrosidase variant (GCase85). GCase85 includes an engineered disulfide, which results in a >6-fold increase in active half-life in human serum and a >21-fold increase in active half-life at lysosomal pH conditions, with similar catalytic properties to those of wild-type and exogenous GCase. Preclinical data indicate that FLT201 could offer a durable treatment for Gaucher disease type 1, addressing unmet needs related to substrate accumulation in tissues poorly treated by current enzyme replacement therapy. The improved stability of the engineered GCase85 variant is predicted to be crucial for FLT201's therapeutic effectiveness.eng
dc.identifier.doi10.1016/j.ymthe.2025.05.003
dc.identifier.issn1525-0016
dc.identifier.urihttp://hdl.handle.net/10400.1/27753
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relation.ispartofMolecular Therapy
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectIn-vivo
dc.subjectReplacement therapy
dc.subjectEnzyme replacement
dc.subjectTransgene product
dc.subjectControl region
dc.subjectTolerance
dc.subjectExpression
dc.subjectGlucocerebrosidase
dc.subjectTransduction
dc.subjectDeficiency
dc.titleFLT201, a novel liver-directed AAV gene therapy candidate for Gaucher disease type 1eng
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue8
oaire.citation.titleMolecular Therapy
oaire.citation.volume33
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameTiscornia
person.givenNameGustavo
person.identifier.ciencia-id7818-59E3-E4EE
person.identifier.orcid0000-0002-1841-5330
person.identifier.scopus-author-id6507863404
relation.isAuthorOfPublication8d2c4950-f020-4c0c-bbbd-52d19e1397a4
relation.isAuthorOfPublication.latestForDiscovery8d2c4950-f020-4c0c-bbbd-52d19e1397a4

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