PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy

Daniel Little, Chiara F. Valori, Chantal A. Mutsaers, Ellen J. Bennett, Matthew Wyles, Basil Sharrack, Pamela J. Shaw, Thomas H. Gillingwater, Mimoun Azzouz, Ke Ning*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNA7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNA7 mice increasing mean survival to 30 days compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNA7 mice and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA.

Original languageEnglish
Pages (from-to)270-277
Number of pages8
JournalMolecular Therapy
Volume23
Issue number2
DOIs
Publication statusPublished - Feb 2015

Keywords / Materials (for Non-textual outputs)

  • MOTOR-NEURON PROTEIN
  • NEUROMUSCULAR-JUNCTION
  • NEGATIVE REGULATION
  • AXON REGENERATION
  • DETERMINING GENE
  • CARDIAC DEFECTS
  • SMN
  • MICE
  • DELETION
  • SMN-DELTA-7

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