title: PTEN depletion decreases disease severity and modestly prolongs survival in a mouse model of spinal muscular atrophy.
abstract: 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 (SMNΔ7) 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 SMNΔ7 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 SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA.
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Little
authors.affiliation: 1] Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK [2] Present address: German Centre for Neurodegenerative Diseases (DZNE), Paul-Ehrlich Strasse, Tübingen, Germany.
authors.forename: Chiara F
authors.initials: CF
authors.lastname: Valori
authors.affiliation: Centre for Integrative Physiology & Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Chantal A
authors.initials: CA
authors.lastname: Mutsaers
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Bennett
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wyles
authors.affiliation: Academic Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospital Foundation Trust, Sheffield, UK.
authors.forename: Basil
authors.initials: B
authors.lastname: Sharrack
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Centre for Integrative Physiology & Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
authors.affiliation: 1] Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK [2] Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Ke
authors.initials: K
authors.lastname: Ning
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D000229:Dependovirus / Q000145:classification / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007273:Injections, Intramuscular; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics*; D014161:Transduction, Genetic
chemical_list: D034741:RNA, Small Interfering; D051059:PTEN Phosphohydrolase