Intravenous Injection of an AAV-PHP.B Vector Encoding Human Acid α-Glucosidase Rescues Both Muscle and CNS Defects in Murine Pompe Disease
| Autor: | Nina Raben, Fengqin Gao, Haiqing Yi, Baodong Sun, Priya S. Kishnani, Jeong-A Lim |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty lcsh:QH426-470 Genetic enhancement glycogen storage Article acid alpha-glucosidase deficiency Virus 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine AAV-PHP.B vector Internal medicine Glycogen storage disease type II Genetics medicine Vector (molecular biology) lcsh:QH573-671 neurological deficits Molecular Biology Glycogen lcsh:Cytology business.industry Pompe disease Skeletal muscle Enzyme replacement therapy medicine.disease Spinal cord gene therapy lcsh:Genetics 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry 030220 oncology & carcinogenesis Molecular Medicine CNS business |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 12, Iss, Pp 233-245 (2019) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| DOI: | 10.1016/j.omtm.2019.01.006 |
| Popis: | 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. Furthermore, we demonstrate that the therapy can help prevent the development of these abnormalities. Keywords: Pompe disease, acid alpha-glucosidase deficiency, gene therapy, AAV-PHP.B vector, glycogen storage, CNS, neurological deficits |
| Databáze: | OpenAIRE |
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