Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS

Kevin D. Foust, Desirée L. Salazar, Shibi Likhite, Laura Ferraiuolo, Dara Ditsworth, Hristelina Ilieva, Kathrin Meyer, Leah Schmelzer, Lyndsey Braun, Don W. Cleveland, Brian K. Kaspar

Research output: Contribution to journalArticle

Abstract

Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.

Original languageEnglish (US)
Pages (from-to)2148-2159
Number of pages12
JournalMolecular Therapy
Volume21
Issue number12
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Dependovirus
Amyotrophic Lateral Sclerosis
Disease Progression
Survival
Motor Neurons
Therapeutics
Neuroglia
Astrocytes
Paralysis
Primates
Small Interfering RNA
Superoxide Dismutase-1
Serogroup
Spinal Cord
Clinical Trials
Mutation
Injections
Amyotrophic lateral sclerosis 1

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Foust, K. D., Salazar, D. L., Likhite, S., Ferraiuolo, L., Ditsworth, D., Ilieva, H., ... Kaspar, B. K. (2013). Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Molecular Therapy, 21(12), 2148-2159. https://doi.org/10.1038/mt.2013.211

Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. / Foust, Kevin D.; Salazar, Desirée L.; Likhite, Shibi; Ferraiuolo, Laura; Ditsworth, Dara; Ilieva, Hristelina; Meyer, Kathrin; Schmelzer, Leah; Braun, Lyndsey; Cleveland, Don W.; Kaspar, Brian K.

In: Molecular Therapy, Vol. 21, No. 12, 2013, p. 2148-2159.

Research output: Contribution to journalArticle

Foust, KD, Salazar, DL, Likhite, S, Ferraiuolo, L, Ditsworth, D, Ilieva, H, Meyer, K, Schmelzer, L, Braun, L, Cleveland, DW & Kaspar, BK 2013, 'Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS', Molecular Therapy, vol. 21, no. 12, pp. 2148-2159. https://doi.org/10.1038/mt.2013.211
Foust, Kevin D. ; Salazar, Desirée L. ; Likhite, Shibi ; Ferraiuolo, Laura ; Ditsworth, Dara ; Ilieva, Hristelina ; Meyer, Kathrin ; Schmelzer, Leah ; Braun, Lyndsey ; Cleveland, Don W. ; Kaspar, Brian K. / Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. In: Molecular Therapy. 2013 ; Vol. 21, No. 12. pp. 2148-2159.
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