Intravenous Injection of an AAV-PHP.B Vector Encoding Human Acid α-Glucosidase Rescues Both Muscle and CNS Defects in Murine Pompe Disease

Molecular Therapy. Methods & Clinical Development
Jeong-A LimBaodong Sun

Abstract

Pompe disease, a severe and often fatal neuromuscular disorder, is caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The disease is characterized by the accumulation of excess glycogen in the heart, skeletal muscle, and CNS. Currently approved enzyme replacement therapy or experimental adeno-associated virus (AAV)-mediated gene therapy has little effect on CNS correction. Here we demonstrate that a newly developed AAV-PHP.B vector can robustly transduce both the CNS and skeletal muscles in GAA-knockout (GAAKO) mice. A single intravenous injection of an AAV-PHP.B vector expressing human GAA under the control of cytomegalovirus (CMV) enhancer-chicken β-actin (CB) promoter into 2-week-old GAAKO mice resulted in widespread GAA expression in the affected tissues. Glycogen contents were reduced to wild-type levels in the brain and heart, and they were significantly decreased in skeletal muscle by the AAV treatment. The histological assay showed no visible glycogen in any region of the brain and spinal cord of AAV-treated mice. In this study, we describe a set of behavioral tests that can detect early neurological deficits linked to extensive lysosomal glycogen accumulation in the CNS of untreated GAAKO mice...Continue Reading

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Citations

Jul 13, 2019·Human Gene Therapy·Pasqualina Colella, Federico Mingozzi
Jun 23, 2019·Human Molecular Genetics·Priya S KishnaniDwight D Koeberl
Dec 5, 2019·Journal of Neuromuscular Diseases·S M SalabarriaM Corti
Mar 28, 2020·International Journal of Molecular Sciences·Anna F FuscoMai K ElMallah
Oct 20, 2020·International Journal of Neonatal Screening·Takaaki SawadaKimitoshi Nakamura
Nov 18, 2020·Metabolic Brain Disease·Dan LiuYong Diao
Nov 13, 2020·Frontiers in Bioengineering and Biotechnology·Robin Reynaud-Dulaurier, Michael Decressac
Jan 10, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Cinzia BragatoMarina Mora
Jul 9, 2020·Molecular Therapy. Methods & Clinical Development·Jeong-A LimBaodong Sun
May 12, 2021·Journal of Human Genetics·Manuel A ViamontePeter B Kang
Jun 5, 2021·Molecular Genetics and Metabolism·Rebecca A GibsonPriya S Kishnani
Aug 20, 2021·Life Science Alliance·Cristin D DavidsonWilliam J Pavan
Jun 2, 2020·Molecular Therapy. Methods & Clinical Development·Pedro Silva-PinheiroCarlo Viscomi
Jan 8, 2020·Molecular Therapy. Methods & Clinical Development·Sang-Oh HanDwight D Koeberl
Oct 12, 2021·Frontiers in Neuroscience·Jonathan M Fischell, Paul S Fishman

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Methods Mentioned

BETA
enzyme replacement therapy
ELISA
transgenic
transfection
Assay

Software Mentioned

Prism
GraphPad

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