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Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model.
Viel, Catherine; Clarke, Jennifer; Kayatekin, Can; Richards, Amy M; Chiang, Ming Sum R; Park, Hyejung; Wang, Bing; Shihabuddin, Lamya S; Sardi, S Pablo.
Afiliación
  • Viel C; Rare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
  • Clarke J; Rare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
  • Kayatekin C; Rare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
  • Richards AM; Genomic Medicine Unit, Sanofi, Framingham, MA, 01701, USA.
  • Chiang MSR; Rare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
  • Park H; US Early Development for Synthetics Platform, Sanofi, Waltham, MA, 02451, USA.
  • Wang B; US Early Development for Synthetics Platform, Sanofi, Waltham, MA, 02451, USA.
  • Shihabuddin LS; Rare and Neurologic Diseases, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA.
  • Sardi SP; 5AM Ventures, Boston, MA, 02116, USA.
Sci Rep ; 11(1): 20945, 2021 10 22.
Article en En | MEDLINE | ID: mdl-34686711
Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson's disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies. Here, we aim to alleviate the lipid storage burden by inhibiting the de novo synthesis of the primary glycosphingolipid substrate of GCase, glucosylceramide (GlcCer). We have previously shown that systemic GCS inhibition reduced GlcCer and glucosylsphingosine (GlcSph) accumulation, slowed α-synuclein buildup in the hippocampus, and improved cognitive deficits. Here, we studied the efficacy of a brain-penetrant clinical candidate GCS inhibitor, venglustat, in mouse models of GBA-related synucleinopathy, including a heterozygous Gba mouse model which more closely replicates the typical GBA-PD patient genotype. Collectively, these data support the rationale for modulation of GCase-related sphingolipid metabolism as a therapeutic strategy for treating GBA-related synucleinopathies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinuclidinas / Carbamatos / Sinucleinopatías / Glucosilceramidasa / Glucosilceramidas / Glucosiltransferasas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinuclidinas / Carbamatos / Sinucleinopatías / Glucosilceramidasa / Glucosilceramidas / Glucosiltransferasas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido