| Autor: |
Charles Harvey Vannoy, Victoria Leroy, Qi Long Lu |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Methods & Clinical Development, Vol 11, Iss , Pp 106-120 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2329-0501 |
| DOI: |
10.1016/j.omtm.2018.10.004 |
| Popis: |
Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein (FKRP) gene mutations are rare disorders that result in a wide spectrum of clinical severity based on the age of onset, the degree of myogenic atrophy, and/or neurologic involvement. There is no cure for any of the FKRP-related disorders, and few options are available for symptom management. Herein, we examine the longitudinal effects of a dose-escalation study to evaluate the safety and therapeutic potential of FKRP gene-replacement therapy in a p.P448L (FKRPP448L) mouse model of MDDG. A recombinant adeno-associated virus (AAV) serotype 9 vector expressing human FKRP (AAV9-FKRP) was systemically administered to FKRPP448L mice at 5 weeks of age, when early onset of the disease is evidenced. A comprehensive analysis of protein and gene expression, histopathology, skeletal muscle function, and cardiorespiratory function was performed over short (9-week) and/or long-term (52-week) study periods. Additional studies assessed the impact of FKRP gene-replacement therapy on lifespan at an advanced stage of disease progression. Results indicate that treatment intervention can restore the biochemical defects in a dose-dependent manner, with potential for improvement in the trajectory of disease progression and extension of the expected lifespan. This study supports the initiation of early-stage clinical trials for FKRP-related disorders. Keywords: muscular dystrophy-dystroglycanopathy, fukutin-related protein, gene therapy |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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