SMA is a progressive disease of the motor neurons and a leading cause of infant mortality. SMA is caused by SMN1 loss. Its paralogue, SMN2, differs from SMN1 by a single substitution at position 6 of exon 7 and produces an unstable protein. SMN2 partially compensates SMN1 loss. Currently, there are three therapies available for SMA. The antisense oligonucleotide nusinersen, and risdiplam promote the inclusion of exon 7 and enable circa 2-fold regulation of SMN levels. The third option is AAV mediated gene therapy, onasemnogene abeparvovec, which can upregulate in the spinal cord the SMN transcript by ~25%. These approaches have limitations which include transient effectiveness, insufficient levels of protein recovery, the need for repeating dosing, and potential long-term toxicity. Genome editing could enable a one-off treatment with preserved endogenous regulatory mechanisms.
Arbab et al. (2023) compared in vitro nearly 80 total nuclease and base editing strategies targeting five regions of SMN2 to induce either posttranscriptional or post-translational regulatory changes in SMN2 to upregulate SMN.
Base editors precisely convert nucleotides without inducing double-strand brakes and resulted in greater SMN protein up-regulation than the nucleases-based therapies. Base editing of exon 7 C6T translated in the greatest up-regulation of SMN protein. Six base editing strategies were able to restore SMN protein levels to wild-type levels in the cellular model. For comparison, a 9-fold increase can be reached with risdiplam, 17-fold with nusinersen, and 41-fold with the top six ABE8e editing strategies, and the latter is comparable with normal expression. AAV9-mediated base editor-based restoration of SMN protein levels provided therapeutic levels of editing in Δ7SMA mice. AAV9-mediated base editor delivery in Δ7SMA mice enabled 87% average T6 >C conversion, improved motor function, coordination and extended average life span. The challenging issue in base editing in the murine model is the fact that the protein restoration is slower than in the other therapeutic approaches mentioned before and may take around 1-3 weeks (Davis et al., 2022). The authors tested a combinational therapeutic strategy with nusinersen and showed improved motor function and extended average life span in Δ7SMA mice compared to heterozygous mice (Arbab et al., 2023).
Key points:
- Approved therapies for Spinal muscular atrophy (SMA) rescue motor function by up-regulation of SMN protein in ways that bypass endogenous SMN regulation, repeated dosing is needed, and effects may be transient.
- Arbab et al. (2023) showed for the first time the feasibility of genome editing as permanently restoring SMN protein levels in cellular and animal models of SMA, with sustained effects on SMA phenotypes.
- SMN restoration with base editing is relatively slow, and best results were reached when using combinational therapy with nusinersen.
References:
Arbab, M., Matuszek, Z., Kray, K. M., Du, A., Newby, G. A., Blatnik, A. J., Raguram, A., Richter, M. F., Zhao, K. T., Levy, J. M., Shen, M. W., Arnold, W. D., Wang, D., Xie, J., Gao, G., Burghes, A. H., & Liu, D. R. (2023). Base editing rescue of spinal muscular atrophy in cells and in mice. Science. https://doi.org/10.1126/science.adg6518
Davis, J. R., Wang, X., Witte, I. P., Huang, T. P., Levy, J. M., Raguram, A., Banskota, S., Seidah, N. G., Musunuru, K., & Liu, D. R. (2022). Efficient in vivo base editing via single adeno-associated viruses with size-optimized genomes encoding compact adenine base editors. Nature Biomedical Engineering, 6(11), 1272–1283. https://doi.org/10.1038/s41551-022-00911-4
Author:
Marina Boziki,Laboratory of Experimental Neurology and Neuroimmunology and Multiple Sclerosis Center, 2nd Neurological University Department, AHEPA General Hospital of Thessaloniki, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
Co-author:
Radu Tanasescu, Department of Neurology, Nottingham Centre for MS and Neuroinflammation, Nottingham University Hospitals NHS Trust, Nottingham, UK
Publish on behalf of the Scientific Panel on Neuroscience/Translational neurology