دورية أكاديمية
أعرض في EDS

AAV9-Mediated Intrastriatal Delivery of GNAO1 Reduces Hyperlocomotion in Gnao1 Heterozygous R209H Mutant Mice.

التفاصيل البيبلوغرافية
العنوان: AAV9-Mediated Intrastriatal Delivery of GNAO1 Reduces Hyperlocomotion in Gnao1 Heterozygous R209H Mutant Mice.
المؤلفون: Roy AJ; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Leipprandt JR; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Patterson JR; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Stoll AC; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Kemp CJ; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Oula ZD; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Mola T; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Batista AR; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Sortwell CE; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Sena-Esteves M; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts., Neubig RR; Department of Pharmacology and Toxicology (A.J.R., J.R.L., R.R.N.), Department of Microbiology and Molecular Genetics (A.J.R.), and Nicholas V. Perricone, M.D., Division of Dermatology, Department of Medicine (R.R.N.), Michigan State University, East Lansing, Michigan; Department of Translational Neuroscience (J.R.P., A.C.S., C.J.K., C.E.S.), Michigan State University, Grand Rapids, Michigan; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan (C.E.S.); and Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research (Z.-T.D.O., T.M., A.R.B., M.S.-E.) and Department of Neurology (Z.-T.D.O., T.M., A.R.B., M.S.-E.), UMass Chan Medical School, Worcester, Massachusetts RNeubig@msu.edu.
المصدر: The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Jul 18; Vol. 390 (2), pp. 250-259. Date of Electronic Publication: 2024 Jul 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics
Original Publication: Baltimore : Williams & Wilkins
مواضيع طبية MeSH: GTP-Binding Protein alpha Subunits, Gi-Go*/genetics , Dependovirus*/genetics , Heterozygote*, Animals ; Mice ; Humans ; Male ; Genetic Vectors/administration & dosage ; Genetic Vectors/genetics ; Hyperkinesis/genetics ; Mutation ; Genetic Therapy/methods ; Mice, Inbred C57BL ; Locomotion/genetics
مستخلص: Mutations in the GNAO1 gene, which encodes the abundant brain G-protein G α o , result in neurologic disorders characterized by developmental delay, epilepsy, and movement abnormalities. There are over 50 mutant alleles associated with GNAO1 disorders; the R209H mutation results in dystonia, choreoathetosis, and developmental delay without seizures. Mice heterozygous for the human mutant allele ( Gnao1 +/R209H ) exhibit hyperactivity in open field tests but no seizures. We developed self-complementary adeno-associated virus serotype 9 (scAAV9) vectors expressing two splice variants of human GNAO1 G α o isoforms 1 (G o A, GNAO1.1 ) and 2 (G o B, GNAO1.2 ). Bilateral intrastriatal injections of either scAAV9- GNAO1.1 or scAAV9- GNAO1.2 significantly reversed mutation-associated hyperactivity in open field tests. GNAO1 overexpression did not increase seizure susceptibility, a potential side effect of GNAO1 vector treatment. This represents the first report of successful preclinical gene therapy for GNAO1 encephalopathy applied in vivo. Further studies are needed to uncover the molecular mechanism that results in behavior improvements after scAAV9-mediated G α o expression and to refine the vector design. SIGNIFICANCE STATEMENT: GNAO1 mutations cause a spectrum of developmental, epilepsy, and movement disorders. Here we show that intrastriatal delivery of scAAV9- GNAO1 to express the wild-type G α o protein reduces the hyperactivity of the Gnao1 +/R209H mouse model, which carries one of the most common movement disorder-associated mutations. This is the first report of a gene therapy for GNAO1 encephalopathy applied in vivo on a patient-allele model.
(Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
المشرفين على المادة: EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
EC 3.6.5.1 (GNAO1 protein, mouse)
0 (GNAO1 protein, human)
تواريخ الأحداث: Date Created: 20240612 Date Completed: 20240718 Latest Revision: 20240819
رمز التحديث: 20240819
DOI: 10.1124/jpet.124.002117
PMID: 38866563
قاعدة البيانات: MEDLINE
الوصف
تدمد:1521-0103
DOI:10.1124/jpet.124.002117