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Page last updated: 22 September 2016


Dr James Sleigh, our Scientific Research Correspondent, reports on Antisense Oligonucleotide (ASO) technology which holds great promise for the treatment of SMA:

The gene therapy, Nusinersen, which specifically acts to increase the amount of SMN protein made by the SMN2 backup gene, has proven safe, well-tolerated, and able to improve motor performance in an interim analysis of Phase III clinical trial data.

SMA patients have low levels of SMN protein in all cells of the body, yet it is the motor neurons that appear to be the cell type most affected by this. Therapies aimed at increasing SMN levels in SMA patients should therefore principally target these cells and associated tissues in order to provide the best chance of success.

Accordingly, Nusinersen is currently injected intrathecally (i.e. directly into the fluid bathing the spinal cord and brain), mechanically delivering it across the blood-brain barrier, which often prevents drugs getting to motor neurons. However, this type of injection is rather invasive and requires specialist expertise. An intravenous injection into the blood would be preferable. Unfortunately, experiments in mice indicate that this sort of administration method does not allow the ASOs to get into the nervous system. Hence, this is why the intrathecal delivery route was chosen for Nusinersen.

New research from the laboratory of Prof. Matthew Wood (University of Oxford, UK) and co-lead by Dr. Suzan Hammond, has shown that combining ASOs with specific nervous system-targeting molecules permits passage of the therapy across the blood-brain barrier.

These molecules, known as PMO internalising peptides, act as homing devices that transport the SMN2 splice-modifying drugs from the blood where they are injected, throughout the body, and, importantly, to the spinal cord and brain.

Single injections of the drug (called Pip6a-PMO) into the blood on the day of birth caused large increases in SMN protein levels throughout the body, which improved the neuromuscular system, increased body weight, and extended lifespan. When SMA mice were given two doses of the drug, on the day of birth and two days later, their average survival improved from 12 days to an unprecedented 456 days – the greatest increase in lifespan reported in SMA mice to date.

The blood brain barrier is not fully formed at the time that Pip6a-PMO was given to the young SMA mice. The researchers therefore administered the drug to healthy adult mice with fully formed and functional barriers. Importantly, the targeting peptides were able to successfully deliver the ASOs to the adult nervous system, which is vital if ASOs are to be used in the future for the treatment of SMA Types affecting a range of ages.

This exciting work, which was part-funded by SMA Support UK (now SMA UK) through SMA Europe, highlights the importance of continued research into ways of improving gene therapy delivery. We are at a very promising time in SMA therapy development, but there is always room for improvement, especially when we do not know for certain the benefit that the therapies currently being tested in clinical trials will provide. This latest research from the Wood Group, suggests that targeting peptides have great potential for improving the potency of gene therapies for SMA, and are likely to become the focus of future research.


Further Information

Scientific Publication from The Wood Laboratory >