2024-03-29T06:37:38Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/111722023-10-13T08:36:27Zcom_20.500.12105_2152com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2153
Repisalud
author
Colella, Pasqualina
author
Sellier, Pauline
author
Gomez, Manuel J
author
Biferi, Maria G
author
Tanniou, Guillaume
author
Guerchet, Nicolas
author
Cohen-Tannoudji, Mathilde
author
Moya-Nilges, Maryse
author
van Wittenberghe, Laetitia
author
Daniele, Natalie
author
Gjata, Bernard
author
Krijnse-Locker, Jacomina
author
Collaud, Fanny
author
Simon-Sola, Marcelo
author
Charles, Severine
author
Cagin, Umut
author
Mingozzi, Federico
funder
French Muscular Dystrophy Association
funder
Unión Europea
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
2020-10-15T09:51:12Z
2020-10-15T09:51:12Z
2020-10-08
EBioMedicine. 2020; 61:103052
http://hdl.handle.net/20.500.12105/11172
33039711
10.1016/j.ebiom.2020.103052
2352-3964
EBioMedicine
Pompe disease (PD) is a neuromuscular disorder caused by deficiency of acidalpha-glucosidase (GAA), leading to motor and respiratory dysfunctions. Available Gaa knock-out (KO) mouse models do not accurately mimic PD, particularly its highly impaired respiratory phenotype.
Here we developed a new mouse model of PD crossing Gaa KOB6;129 with DBA2/J mice. We subsequently treated Gaa KODBA2/J mice with adeno-associated virus (AAV) vectors expressing a secretable form of GAA (secGAA).
Male Gaa KODBA2/J mice present most of the key features of the human disease, including early lethality, severe respiratory impairment, cardiac hypertrophy and muscle weakness. Transcriptome analyses of Gaa KODBA2/J, compared to the parental Gaa KOB6;129 mice, revealed a profoundly impaired gene signature in the spinal cord and a similarly deregulated gene expression in skeletal muscle. Muscle and spinal cord transcriptome changes, biochemical defects, respiratory and muscle function in the Gaa KODBA2/J model were significantly improved upon gene therapy with AAV vectors expressing secGAA.
These data show that the genetic background impacts on the severity of respiratory function and neuroglial spinal cord defects in the Gaa KO mouse model of PD. Our findings have implications for PD prognosis and treatment, show novel molecular pathophysiology mechanisms of the disease and provide a unique model to study PD respiratory defects, which majorly affect patients.
This work was supported by Genethon, the French Muscular Dystrophy Association (AFM), the European Commission (grant nos. 667751, 617432, and 797144), and Spark Therapeutics.
eng
Gene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects.
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/11172/1/GeneTherapyWithSecreted_2020.pdf
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GeneTherapyWithSecreted_2020.pdf
URL
https://repisalud.isciii.es/bitstream/20.500.12105/11172/6/GeneTherapyWithSecreted_2020.pdf.txt
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GeneTherapyWithSecreted_2020.pdf.txt