Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A
| Autor: | John Forsayeth, Piotr Hadaczek, Vivek Sudhakar, Josefina Casas, Jesús Avila, Beatriz Soto-Huelin, Seng H. Cheng, Maria Dolores Ledesma, Haifeng Chen, Krystof S. Bankiewicz, Xingxuan He, Jerónimo Jurado-Arjona, John Bringas, Lluis Samaranch, Edward H. Schuchman, Azucena Pérez-Cañamás |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Fundación Ramón Areces |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Primates
Ceramide Knockout Genetic enhancement Inflammation Neurodegenerative Pharmacology Motor Activity Serogroup Medical and Health Sciences Article Type A Viral vector Injections Mice chemistry.chemical_compound Rare Diseases Niemann-Pick Disease Genetics medicine Animals Humans Transgenes Mice Knockout business.industry Neurodegeneration Neurosciences Brain Gene Therapy General Medicine Genetic Therapy Biological Sciences Dependovirus Niemann-Pick Disease Type A medicine.disease Brain Disorders Sphingomyelin Phosphodiesterase chemistry Liver Neurological medicine.symptom Acid sphingomyelinase Niemann–Pick disease Sphingomyelin business Biotechnology medicine.drug |
| Zdroj: | Sci Transl Med Digital.CSIC. Repositorio Institucional del CSIC instname Science translational medicine, vol 11, iss 506 |
| Popis: | Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders. © 2019 The Authors. This work was supported by Wylder Nation Foundation and by grants from Spanish Ministry of Economy and Competitivity (SAF-2014-57539-R and SAF2017-87698-R) to M.D.L. and from NIH-NINDS (R01NS073940) to K.S.B. A.P-C was a recipient of the FPU pre-doctoral fellowship from the Spanish Ministry of Economy and Competitivity. L.S. was a recipient of the Edward H. Schuchman Research Fellowship from the National Niemann-Pick Disease Foundation. E.H.S. and X.H. were supported by a MERIT award from the NIH (R37 HD28607) to E.H.S. |
| Databáze: | OpenAIRE |
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