Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy

Rachel A. Powis, Evangelia Karyka, Penelope Boyd, Julien Come, Ross A. Jones, Yinan Zheng, Eva Szunyogova, Ewout J. N. Groen, Gillian Hunter, Derek Thomson, Thomas M. Wishart, Catherina G. Becker, Simon H. Parson, Cecile Martinat, Mimoun Azzouz, Thomas H. Gillingwater

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Abstract

The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell–derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno-associated virus serotype 9–UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA.
Original languageEnglish
Article numbere87908
Pages (from-to)1-16
Number of pages16
JournalJCI Insight
Volume1
Issue number11
DOIs
Publication statusPublished - 21 Jul 2016

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Spinal Muscular Atrophy
Motor Neurons
Ubiquitin
Dependovirus
Zebrafish
Pathology
Therapeutics
Neuromuscular Diseases
Ubiquitination
Enzymes
Genetic Therapy
Axons
Weight Loss
Proteins
Homeostasis
Survival

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Powis, R. A., Karyka, E., Boyd, P., Come, J., Jones, R. A., Zheng, Y., ... Gillingwater, T. H. (2016). Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI Insight, 1(11), 1-16. [e87908]. https://doi.org/10.1172/jci.insight.87908

Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. / Powis, Rachel A.; Karyka, Evangelia; Boyd, Penelope; Come, Julien; Jones, Ross A.; Zheng, Yinan; Szunyogova, Eva; Groen, Ewout J. N.; Hunter, Gillian; Thomson, Derek; Wishart, Thomas M.; Becker, Catherina G.; Parson, Simon H.; Martinat, Cecile; Azzouz, Mimoun; Gillingwater, Thomas H.

In: JCI Insight, Vol. 1, No. 11, e87908, 21.07.2016, p. 1-16.

Research output: Contribution to journalArticle

Powis, RA, Karyka, E, Boyd, P, Come, J, Jones, RA, Zheng, Y, Szunyogova, E, Groen, EJN, Hunter, G, Thomson, D, Wishart, TM, Becker, CG, Parson, SH, Martinat, C, Azzouz, M & Gillingwater, TH 2016, 'Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy', JCI Insight, vol. 1, no. 11, e87908, pp. 1-16. https://doi.org/10.1172/jci.insight.87908
Powis RA, Karyka E, Boyd P, Come J, Jones RA, Zheng Y et al. Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI Insight. 2016 Jul 21;1(11):1-16. e87908. https://doi.org/10.1172/jci.insight.87908
Powis, Rachel A. ; Karyka, Evangelia ; Boyd, Penelope ; Come, Julien ; Jones, Ross A. ; Zheng, Yinan ; Szunyogova, Eva ; Groen, Ewout J. N. ; Hunter, Gillian ; Thomson, Derek ; Wishart, Thomas M. ; Becker, Catherina G. ; Parson, Simon H. ; Martinat, Cecile ; Azzouz, Mimoun ; Gillingwater, Thomas H. / Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. In: JCI Insight. 2016 ; Vol. 1, No. 11. pp. 1-16.
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abstract = "The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell–derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno-associated virus serotype 9–UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA.",
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AU - Szunyogova, Eva

AU - Groen, Ewout J. N.

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N1 - Acknowledgments Blood biochemistry analysis and serum analysis were performed by the Easter Bush Pathology Department, University of Edinburgh. Animal husbandry was performed by Centre for Integrative Physiology bio-research restructure technical staff, University of Edinburgh. Assistance with intravenous injections was provided by Ian Coldicott (University of Sheffield) and Hannah Shorrock (University of Edinburgh). Human blood cDNA was a gift to GH from Kathy Evans, University of Edinburgh. Imaging was performed at the IMPACT imaging facility, University of Edinburgh, with technical assistance from Anisha Kubasik-Thayil. The authors would also like to thank Lyndsay Murray for technical discussions relating to qRT-PCR analysis. This work was supported by funding from the SMA Trust and the Anatomical Society (via grants to THG); the Euan MacDonald Centre for Motor Neurone Disease Research (via grants to THG and SHP); the Wellcome Trust (via grants to EJNG and THG); Muscular Dystrophy UK (via grants to THG and CGB); a Elphinstone Scholarship from the University of Aberdeen (to SHP); and The French Muscular Dystrophy Association (via grants to CM and JC).

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N2 - The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell–derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno-associated virus serotype 9–UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA.

AB - The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell–derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno-associated virus serotype 9–UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA.

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