Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy
- Powis, R.A., Karyka, E., Boyd, P., Côme, J., Jones, R.A., Zheng, Y., Szunyogova, E., Groen, E.J., Hunter, G., Thomson, D., Wishart, T.M., Becker, C.G., Parson, S.H., Martinat, C., Azzouz, M., Gillingwater, T.H.
- JCI insight 1: e87908 (Journal)
- Registered Authors
- Becker, Catherina G., Boyd, Penelope
- Neuroscience, Therapeutics
- MeSH Terms
- Gene Knockdown Techniques
- Genetic Therapy*
- Mice, Knockout
- Motor Neurons/cytology
- Muscular Atrophy, Spinal/therapy*
- Ubiquitin-Activating Enzymes/genetics*
- 27699224 Full text @ JCI Insight
Powis, R.A., Karyka, E., Boyd, P., Côme, J., Jones, R.A., Zheng, Y., Szunyogova, E., Groen, E.J., Hunter, G., Thomson, D., Wishart, T.M., Becker, C.G., Parson, S.H., Martinat, C., Azzouz, M., Gillingwater, T.H. (2016) Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy. JCI insight. 1:e87908.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes