AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study

AAV-mediated gene therapy holds promise for the treatment of lysosomal storage diseases (LSDs), some of which are already in clinical trials. Yet, ultra-rare subtypes of LSDs, such as some glycoproteinoses, have lagged. Here, we report on a long-term safety and efficacy preclinical study conducted i...

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Autores principales:	Huimin Hu, Rosario Mosca, Elida Gomero, Diantha van de Vlekkert, Yvan Campos, Leigh E. Fremuth, Scott A. Brown, Jason A. Weesner, Ida Annunziata, Alessandra d’Azzo
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	lysosomal storage disease galactosialidosis protective protein cathepsin A lysosomal multienzyme complex AAV-mediated gene therapy Genetics QH426-470 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/4f4d2859730e48d497c3d91716323069
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spelling	oai:doaj.org-article:4f4d2859730e48d497c3d917163230692021-12-02T05:01:47ZAAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study2329-050110.1016/j.omtm.2021.10.007https://doaj.org/article/4f4d2859730e48d497c3d917163230692021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2329050121001649https://doaj.org/toc/2329-0501AAV-mediated gene therapy holds promise for the treatment of lysosomal storage diseases (LSDs), some of which are already in clinical trials. Yet, ultra-rare subtypes of LSDs, such as some glycoproteinoses, have lagged. Here, we report on a long-term safety and efficacy preclinical study conducted in the murine model of galactosialidosis, a glycoproteinosis caused by a deficiency of protective protein/cathepsin A (PPCA). One-month-old Ctsa−/− mice were injected intravenously with a high dose of a self-complementary AAV2/8 vector expressing human CTSA in the liver. Treated mice, examined up to 12 months post injection, appeared grossly indistinguishable from their wild-type littermates. Sustained expression of scAAV2/8-CTSA in the liver resulted in the release of the therapeutic precursor protein in circulation and its widespread uptake by cells in visceral organs and the brain. Increased cathepsin A activity resolved lysosomal vacuolation throughout the affected organs and sialyl-oligosacchariduria. No signs of hyperplasia or inflammation were detected in the liver up to a year of age. Clinical chemistry panels, blood cell counts, and T cell immune responses were normal in all treated animals. These results warrant a close consideration of this gene therapy approach for the treatment of galactosialidosis, an orphan disease with no cure in sight.Huimin HuRosario MoscaElida GomeroDiantha van de VlekkertYvan CamposLeigh E. FremuthScott A. BrownJason A. WeesnerIda AnnunziataAlessandra d’AzzoElsevierarticlelysosomal storage diseasegalactosialidosisprotective protein cathepsin Alysosomal multienzyme complexAAV-mediated gene therapyGeneticsQH426-470CytologyQH573-671ENMolecular Therapy: Methods & Clinical Development, Vol 23, Iss , Pp 644-658 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	lysosomal storage disease galactosialidosis protective protein cathepsin A lysosomal multienzyme complex AAV-mediated gene therapy Genetics QH426-470 Cytology QH573-671
spellingShingle	lysosomal storage disease galactosialidosis protective protein cathepsin A lysosomal multienzyme complex AAV-mediated gene therapy Genetics QH426-470 Cytology QH573-671 Huimin Hu Rosario Mosca Elida Gomero Diantha van de Vlekkert Yvan Campos Leigh E. Fremuth Scott A. Brown Jason A. Weesner Ida Annunziata Alessandra d’Azzo AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study
description	AAV-mediated gene therapy holds promise for the treatment of lysosomal storage diseases (LSDs), some of which are already in clinical trials. Yet, ultra-rare subtypes of LSDs, such as some glycoproteinoses, have lagged. Here, we report on a long-term safety and efficacy preclinical study conducted in the murine model of galactosialidosis, a glycoproteinosis caused by a deficiency of protective protein/cathepsin A (PPCA). One-month-old Ctsa−/− mice were injected intravenously with a high dose of a self-complementary AAV2/8 vector expressing human CTSA in the liver. Treated mice, examined up to 12 months post injection, appeared grossly indistinguishable from their wild-type littermates. Sustained expression of scAAV2/8-CTSA in the liver resulted in the release of the therapeutic precursor protein in circulation and its widespread uptake by cells in visceral organs and the brain. Increased cathepsin A activity resolved lysosomal vacuolation throughout the affected organs and sialyl-oligosacchariduria. No signs of hyperplasia or inflammation were detected in the liver up to a year of age. Clinical chemistry panels, blood cell counts, and T cell immune responses were normal in all treated animals. These results warrant a close consideration of this gene therapy approach for the treatment of galactosialidosis, an orphan disease with no cure in sight.
format	article
author	Huimin Hu Rosario Mosca Elida Gomero Diantha van de Vlekkert Yvan Campos Leigh E. Fremuth Scott A. Brown Jason A. Weesner Ida Annunziata Alessandra d’Azzo
author_facet	Huimin Hu Rosario Mosca Elida Gomero Diantha van de Vlekkert Yvan Campos Leigh E. Fremuth Scott A. Brown Jason A. Weesner Ida Annunziata Alessandra d’Azzo
author_sort	Huimin Hu
title	AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study
title_short	AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study
title_full	AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study
title_fullStr	AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study
title_full_unstemmed	AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study
title_sort	aav-mediated gene therapy for galactosialidosis: a long-term safety and efficacy study
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/4f4d2859730e48d497c3d91716323069
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AAV-mediated gene therapy for galactosialidosis: A long-term safety and efficacy study

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