Krabbe disease successfully treated via monotherapy of intrathecal gene therapy
Autor: | Ernesto R. Bongarzone, Charles A. Assenmacher, G. Diane Shelton, Keiko Miyadera, Gary P. Swain, Charles H. Vite, Xuntian Jiang, Erik Lykken, Duc Nguyen, Jill Pesayco Salvador, Jessica H. Bagel, Patricia O'Donnell, Arielle Ostrager, Steven J. Gray, Rebecka S. Hess, Mark S. Sands, Allison M. Bradbury, Daniel S. Ory, Ian J. Hendricks |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
medicine.medical_treatment Genetic enhancement Inflammation Hematopoietic stem cell transplantation Cisterna magna 03 medical and health sciences Dogs 0302 clinical medicine Galactosylceramidase medicine Animals business.industry Leukodystrophy Genetic Therapy General Medicine Dependovirus medicine.disease Leukodystrophy Globoid Cell Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Peripheral nervous system Immunology Krabbe disease medicine.symptom business Research Article |
Zdroj: | J Clin Invest |
ISSN: | 1558-8238 0021-9738 |
Popis: | Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased GALC enzyme activity, normalized psychosine concentration, improved myelination, and attenuated inflammation in both the CNS and PNS. Moreover, AAV-mediated therapy successfully prevented clinical neurological dysfunction, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs. Furthermore, we found that a 5-fold lower dose resulted in an attenuated form of disease, indicating that sufficient dosing is critical. Finally, postsymptomatic therapy with high-dose AAV9 also significantly extended lifespan, signifying a treatment option for patients for whom HSCT is not applicable. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or postsymptomatically. |
Databáze: | OpenAIRE |
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