Liver-Targeted AAV8 Gene Therapy Ameliorates Skeletal and Cardiovascular Pathology in a Mucopolysaccharidosis IVA Murine Model
| Autor: | Shunji Tomatsu, Kazuki Sawamoto, Molly Stapleton, Shaukat Khan, Subha Karumuthil-Melethil, Olivier Danos, Joseph T. Bruder |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty lcsh:QH426-470 Keratan sulfate Genetic enhancement Mucopolysaccharidosis skeletal dysplasia MPS IVA Article Mucopolysaccharidosis Type IVA Virus 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system cardiovascular disease Internal medicine Genetics medicine lcsh:QH573-671 Molecular Biology keratan sulfate lcsh:Cytology business.industry Sulfatase AAV medicine.disease lcsh:Genetics 030104 developmental biology Endocrinology liver targeting chemistry Dysplasia 030220 oncology & carcinogenesis Molecular Medicine GALNS business |
| Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 18, Iss, Pp 50-61 (2020) |
| ISSN: | 2329-0501 |
| DOI: | 10.1016/j.omtm.2020.05.015 |
| Popis: | Mucopolysaccharidosis type IVA (MPS IVA) is due to the deficiency of GALNS (N-acetylgalactosamine 6-sulfate sulfatase) and is characterized by systemic skeletal dysplasia. We have evaluated adeno-associated virus 8 (AAV8) vectors expressing different forms of human GALNS under a liver-specific promoter. The vectors were delivered intravenously into 4-week-old MPS IVA knockout (KO) and immune tolerant (MTOL) mice at a dose of 5 × 1013 genome copies (GC)/kg. These mice were monitored for 12 weeks post-injection. GALNS enzyme activity was elevated significantly in plasma of all treated mice at 2 weeks post-injection. The activity observed was 4- to 19-fold higher than that in wild-type mice and was maintained throughout the monitoring period. Treatment with AAV vectors resulted in a reduction of keratan sulfate (KS) levels in plasma to normal levels 2 weeks post-injection, which were maintained until necropsy. Both vectors reduced the storage in articular cartilage, ligaments, and meniscus surrounding articular cartilage and growth plate region as well as heart muscle and valves. Our results suggest that the continuous presence of high levels of circulating enzyme increases the penetration into bone and heart and reduces the KS level, thereby improving storage in these regions. The current data support a strategy for developing a novel treatment to address the bone and heart disease in MPS IVA using AAV gene therapy. Graphical Abstract Adeno-associated virus (AAV) gene delivery is a promising approach for many diseases, but implementation in bone is hampered by the need for delivering AAV to the avascular cartilage. Unfortunately, most conventional, non-modified AAV vectors penetrate the cartilage poorly. The proposed method with marked expression of gene product may ameliorate bone lesions. |
| Databáze: | OpenAIRE |
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