Intravenous Injection of an AAV-PHP.B Vector Encoding Human Acid α-Glucosidase Rescues Both Muscle and CNS Defects in Murine Pompe Disease
| العنوان: | Intravenous Injection of an AAV-PHP.B Vector Encoding Human Acid α-Glucosidase Rescues Both Muscle and CNS Defects in Murine Pompe Disease |
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| المؤلفون: | Nina Raben, Fengqin Gao, Haiqing Yi, Baodong Sun, Priya S. Kishnani, Jeong-A Lim |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 12, Iss, Pp 233-245 (2019) Molecular Therapy. Methods & Clinical Development |
| بيانات النشر: | Elsevier BV, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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 |
| تدمد: | 2329-0501 |
| DOI: | 10.1016/j.omtm.2019.01.006 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c456e91a24b288f5fdaf414228066cc8 https://doi.org/10.1016/j.omtm.2019.01.006 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c456e91a24b288f5fdaf414228066cc8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23290501 |
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| DOI: | 10.1016/j.omtm.2019.01.006 |