Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy
Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associ...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050116301899 |
| _version_ | 1811200397095731200 |
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| author | Nicole Armbruster Annalisa Lattanzi Matthieu Jeavons Laetitia Van Wittenberghe Bernard Gjata Thibaut Marais Samia Martin Alban Vignaud Thomas Voit Fulvio Mavilio Martine Barkats Ana Buj-Bello |
| author_facet | Nicole Armbruster Annalisa Lattanzi Matthieu Jeavons Laetitia Van Wittenberghe Bernard Gjata Thibaut Marais Samia Martin Alban Vignaud Thomas Voit Fulvio Mavilio Martine Barkats Ana Buj-Bello |
| author_sort | Nicole Armbruster |
| collection | DOAJ |
| description | Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery. |
| first_indexed | 2024-04-12T02:02:44Z |
| format | Article |
| id | doaj.art-c3375dc222574ce59427a986034859f1 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-12T02:02:44Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-c3375dc222574ce59427a986034859f12022-12-22T03:52:37ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012016-01-013C10.1038/mtm.2016.60Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophyNicole Armbruster0Annalisa Lattanzi1Matthieu Jeavons2Laetitia Van Wittenberghe3Bernard Gjata4Thibaut Marais5Samia Martin6Alban Vignaud7Thomas Voit8Fulvio Mavilio9Martine Barkats10Ana Buj-Bello11INSERM UMR 951, Evry, FranceINSERM UMR 951, Evry, FranceINSERM UMR 951, Evry, FranceGenethon, Evry, FranceGenethon, Evry, FranceCenter of Research in Myology, INSERM UMRS 974, CNRS FRE 3617, Institut de Myologie, Université Pierre et Marie Curie Paris 6, Paris, FranceGenethon, Evry, FranceGenethon, Evry, FranceCenter of Research in Myology, INSERM UMRS 974, CNRS FRE 3617, Institut de Myologie, Université Pierre et Marie Curie Paris 6, Paris, FranceINSERM UMR 951, Evry, FranceCenter of Research in Myology, INSERM UMRS 974, CNRS FRE 3617, Institut de Myologie, Université Pierre et Marie Curie Paris 6, Paris, FranceINSERM UMR 951, Evry, FranceSpinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery.http://www.sciencedirect.com/science/article/pii/S2329050116301899 |
| spellingShingle | Nicole Armbruster Annalisa Lattanzi Matthieu Jeavons Laetitia Van Wittenberghe Bernard Gjata Thibaut Marais Samia Martin Alban Vignaud Thomas Voit Fulvio Mavilio Martine Barkats Ana Buj-Bello Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy Molecular Therapy: Methods & Clinical Development |
| title | Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy |
| title_full | Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy |
| title_fullStr | Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy |
| title_full_unstemmed | Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy |
| title_short | Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy |
| title_sort | efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scaav9 smn1 vector in a mouse model of spinal muscular atrophy |
| url | http://www.sciencedirect.com/science/article/pii/S2329050116301899 |
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