Chaperone-mediated gene therapy with recombinant AAV-PPCA in a new mouse model of type I sialidosis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Bonten, Erik J.¹  Yogalingam, Gouri¹  Hu, Huimin¹  Gomero, Elida¹  van de Vlekkert, Diantha¹  d'Azzo, Alessandra¹ 

[1] St Jude Childrens Res Hosp, Dept Genet, Memphis, TN 38105 USA

关键词: AAV;    Chaperone-mediated therapy;    Gene therapy;    Lysosomal storage disease;    NEU1;    Sialidosis;   

DOI  :  10.1016/j.bbadis.2013.06.002

来源: Elsevier

【 摘 要 】

The lysosomal storage disease sialidosis is caused by a primary deficiency of the sialidase N-acetyl-alpha-neuraminidase-1 (NEW). Patients with type I sialidosis develop an attenuated, non-neuropathic form of the disease also named cherry red spot myoclonus syndrome, with symptoms arising during juvenile/ adult age. NEW requires binding to its chaperone, protective protein/cathepsin A (PPCA), for lysosomal compartmentalization, stability and catalytic activation. We have generated a new mouse model of type I sialidosis that ubiquitously expresses a NEU1 variant carrying a V54M amino acid substitution identified in an adult patient with type I sialidosis. Mutant mice developed signs of lysosomal disease after 1 year of age, predominantly in the kidney, albeit low residual NEW activity was detected in most organs and cell types. We demonstrate that the activity of the mutant enzyme could be effectively increased in all systemic tissues by chaperone-mediated gene therapy with a liver-tropic recombinant AAV2/8 vector expressing PPCA. This resulted in clear amelioration of the disease phenotype. These results suggest that at least some of the NEU1 mutations associated with type I sialidosis may respond to PPCA-chaperone-mediated gene therapy. Published by Elsevier B.V.

【 授权许可】

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