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

• Published in: Molecular therapy. Methods & clinical development Vol. 23; pp. 644 - 658
• Main Authors: Hu, Huimin, Mosca, Rosario, Gomero, Elida, van de Vlekkert, Diantha, Campos, Yvan, Fremuth, Leigh E., Brown, Scott A., Weesner, Jason A., Annunziata, Ida, d’Azzo, Alessandra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.12.2021; American Society of Gene & Cell Therapy; Elsevier
• Subjects: AAV-mediated gene therapy; galactosialidosis; lysosomal multienzyme complex; lysosomal storage disease; Original; protective protein cathepsin A; galactosialidosis; protective protein cathepsin A; AAV-mediated gene therapy; lysosomal storage disease; lysosomal multienzyme complex
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2021.10.007

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. [Display omitted] d’Azzo and colleagues describe a long-term safety and efficacy preclinical study conducted in the mouse model of galactosialidosis, using an AAV-mediated gene therapy approach. Galactosialidosis is an orphan lysosomal storage disease caused by a primary defect of the protective protein/cathepsin A and secondary deficiency of neuraminidase 1 and β-galactosidase.