Nusinersen has gained regulatory approval for the treatment of SMA in the US and Europe, while several other drugs, such as Zolgensma, have shown promise in clinical trials with SMA patients.

Nevertheless, it is important that researchers continue to identify and assess the potential effectiveness of additional treatments and delivery methods for SMA, so that in the future, patients will benefit from the best possible therapy regime. Indeed, there is considerable pre-clinical evidence from mouse models of SMA that a combinatorial approach, i.e. when more than one drug is administered, is likely to be most effective at treating the condition.

Nusinersen is an antisense oligonucleotide that acts as a molecular patch to increase the amount of SMN protein made by the SMN2 backup gene. It does this by binding to a short, but very specific, region of the SMN2 template, known as RNA, that is used to make SMN protein.

A number of different regions of SMN2 determine how much SMN protein is made. Researchers are thus creating and testing new antisense oligonucleotides, similar in design to nusinersen, that target these distinct regions.

In this vein, Audrey Winkelsas (Prof. Matthew Wood Laboratory, University of Oxford and Prof. Kenneth Fischbeck Laboratory, National Institutes of Health, USA) presented some of her PhD research into such a novel antisense oligonucleotide strategy.

SMN2 RNA has very specific information that is used to create SMN protein, but it also possesses additional information that controls how frequently SMN protein is made. Some of this information is contained within a region known as the “5 prime UTR” and this is the part of SMN2 that Ms. Winkelsas has been targeting with a range of different antisense oligonucleotides.

Ms. Winkelsas showed that targeting the “5 primer UTR” with antisense oligonucleotides was able to increase SMN protein levels in a cellular model of SMA. Her results indicate that this increase is likely caused by an enhanced stability of the SMN2 RNA.

This is a strategy that is likely to improve the effectiveness of nusinersen, as it increases the availability of the nusinersen target, i.e. SMN2 RNA. Therefore Ms. Winklesas tested nusinersen with and without her new antisense oligonucleotide and showed that together they lead to the production of more SMN protein than nusinersen alone.

This work provides additional evidence that a combinatorial therapy approach is likely to provide the greatest benefit in SMA patients and that using multiple antisense oligonucleotides is possibly a feasible tactic.

Over the years, it has come to light in mouse models of SMA that the earlier that treatment is provided, the greater the therapeutic effect is likely to be. To take this one step further, Dr. Yu-Ting Huang (Prof. Thomas Gillingwater Laboratory, University of Edinburgh) has developed a project to test therapy delivery to SMA mice before they are born (known as in utero treatment).

Dr. Huang is making use of a protein-linked antisense oligonucleotide, similar to nusinersen, that has an enhanced ability to boost SMN protein levels in the brain and spinal cord of mice. The therapy will be injected directly into the abdomen or nervous system of pre-birth pups to determine whether increasing SMN protein levels before pups are born can yield greater therapeutic effects than when administered after birth.

While there is a great deal of research that is required before a strategy such as this is proven to be both safe and effective, pre-clinical proof-of-concept projects such as these will be vital in paving the way for future clinical developments for SMA and other diseases. We hope to be able to report on the progress of this research in the years to come.

SMA is primarily a nervous system disease and it mainly affects the lower motor neurons, which connect the brain and spinal cord to muscles, allowing conscious muscle contraction. Nonetheless, over the last decade or so, it has become increasingly clear that other cell types and tissues may be affected by very low SMN protein levels, such as those observed in the most severe forms of the disease.

Extending the cell / tissue types potentially impacted by SMA, Ms. Hazel Allardyce (Prof. Simon Parson Laboratory, University of Aberdeen) presented some of her recent findings on defects observed in kidneys of SMA mice.

SMA kidneys were shown to be disproportionately smaller at early symptomatic ages, with major reductions in blood vessel number and complexity. Moreover, kidneys from SMA mice had less than half the number of nephrons than healthy control mice.

Nephrons are the main functional structures of the kidney and their number is thought to be set during kidney development. Ms. Allardyce therefore pointed out that if problems occur in the kidney before treatment, then it is unlikely that nephron number will recover to normal levels.

While defects in cells and tissues other than motor neurons appear to be much more common in mouse models of SMA than in SMA patients, research into non-motor neuron defects is important in the era of nusinersen and other potential therapies. That is because such drugs are frequently targeted to the nervous system, and therefore, if successful, may begin to reveal symptoms in additional parts of the body as the disease progresses.