Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase.

Sci Transl Med 2017 Nov;9(418)

INTEGRARE, Genethon, Inserm, Univ Evry, Université Paris-Saclay, 91002 Evry, France.

Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the transgenes to Gaa knockout (Gaa) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector-mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aam6375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826611PMC

Still can't find the full text of the article?

Sign up to send a request to the authors directly.
November 2017
46 Reads

Publication Analysis

Top Keywords

pompe disease
20
glycogen accumulation
12
secretable gaa
8
gaa mice
8
acid α-glucosidase
8
pathological glycogen
8
aav vectors
8
gaa
8
disease
6
glycogen
5
disease therapeutic
4
therapeutic gene
4
gene transfer
4
mice model
4
gaa knockout
4
knockout gaa
4
accumulation multiple
4
model pompe
4
transfer liver
4
nervous system
4

Altmetric Statistics

References

(Supplied by CrossRef)
New therapeutic approaches for Pompe disease: Enzyme replacement therapy and beyond
Kishnani et al.
Pediatr. Endocrinol. Rev. 2014

Similar Publications