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SMA Support UK at the International Scientific Congress on SMA 2018

27 February 2018

Organised by SMA Europe with Brunhilde Wirth (University of Cologne, Germany) as the Scientific Chair, the first International Scientific Congress on SMA was held at Jagiellonian University in Kraków, Poland from 25th-27th January 2018. More than 100 laboratory and clinical SMA studies were presented by researchers from across the world to over 450 attendees.

In seven different sessions, the presentations and posters highlighted a broad range of SMA-related topics covering the importance of defects in cells other than motor nerve cells, the potential for combining treatments for improved therapeutic outcome, and the latest clinical trial updates. Below, we summarise and discuss some of the key presentations on these important topics.

Further Information

1. The importance of non-motor neuron defects

Motor neurons, which are the nerve cells that connect the brain and spinal cord to muscles to allow conscious muscle contraction, are the main cell type affected by SMA. Reduced levels of survival motor neuron (SMN) protein result in degeneration of motor neurons, leading to the muscle wasting that is characteristic of the disease.

It remains unclear exactly why motor neurons are the main cell type affected by the disease; however, over the last decade, research on mouse models of SMA indicates that the motor neurons may not be the only cells affected by reduced availability of SMN protein.

In SMA mice, which have very low levels of SMN protein, a number of studies have found that cells other than motor neurons can show the negative effects of disease (i.e. pathology). Consistent with non-motor neuron cells and tissues playing a role in disease, it has been known for some time that SMA therapies must be targeted to different areas of the body in mice to get the best improvements in the disease (click here for more information).

Charlotte Sumner (John Hopkins Medical Centre, USA) opened the session on non-motor pathologies in SMA by providing an introduction to the theme and discussing some of the past published research on the topic. Prof. Sumner highlighted that the SMN protein can be found in most cells and tissues in the body, and posed the question – is SMA therefore expected to affect cells other than just the motor neurons?

Melissa Bowerman (Keele University, UK) followed by presenting interesting work from her laboratory indicating that reduced SMN levels can negatively impact something called circadian rhythms. These rhythms provide a natural synchronicity of the body’s biological processes to the light/dark (night/day) cycles over a 24 hour period. Amongst many things, they help us to be able to sleep at night and be more awake during daylight. Work from the Bowerman Laboratory showed that circadian rhythm genes are perturbed in SMA mice, and that by tightly controlling light levels, these perturbations can be returned to normal, improving the health of SMA mice. These effects were shown to be in cells outside of the nervous system. SMN-related disruptions in wake/sleep rhythms could therefore contribute to the sleep disorders that are reported as being common in children with SMA.

Simon Parson (University of Aberdeen, UK) continued the discussion by presenting his latest findings on the heart of SMA mice. Prof. Parson has previously shown that blood vessels are affected in severe SMA mice and patients with SMA Type 1 (click here for more information). His team have now found that hearts of severe SMA mice display delayed development, increased signs of cell death, and pooling of blood in certain compartments. These deficiencies occur early in the model, get worse with age, and are likely to contribute to the drastically reduced lifespan of these animals.

Finally, Rashmi Kothary (University of Ottawa, Canada) presented work from his laboratory indicating that SMA mice develop symptoms similar to non-alcoholic fatty liver disease as they age. The livers of SMA mice showed signs of damage and impaired function, suggesting that altered metabolism could play a role in SMA.

It is clear from many years’ research on SMA mice that low SMN levels can have a negative effect on a broad array of cell and tissue types in these animals. This has potential implications for the development of therapies that aim to increase SMN protein levels, as it is likely they will have to do so throughout the body in order to generate the best therapeutic effect.

However, mice are very different from us humans, and not all findings from SMA models will necessarily be of direct relevance to the human condition. Mice used in the laboratory to study SMA have very low levels of the SMN protein, and are thought by many scientists to be modelling the most severe forms of the human disease. Many of the non-motor defects found in these mice are therefore unlikely to be involved in disease in the vast majority of SMA patients. Some of the reported issues in SMA mice have been confirmed in selected SMA Type 1 patients; however, they do not occur with the same regularity as seen in SMA mice

While mice may not always perfectly model humans, it remains important to study the effects of reduced SMN protein levels across a range of tissues to improve understanding of how and where the SMN protein may be important. The more we understand about the body’s requirements for SMN, the better we will be able to target therapies to the correct locations.


2. Can combining therapies lead to greater improvements?

The antisense oligonucleotide nusinersen (marketed as SpinrazaTM) has been approved for the treatment of SMA (click here for more information), but there are a number of other drugs and therapies currently being trialled for the disease that may also prove effective (see our Drug Pipeline for further information).

Download drug pipeline

It is therefore possible that multiple drugs with promise for SMA could one day be used simultaneously. Researchers in the laboratory have been testing this idea of a combinatorial approach to treating SMA. Early indications are showing that a number of different therapies provide greater benefit to SMA mice when tested together compared to when used in isolation (click here for an example).

Christian Lorson (University of Missouri, USA) presented work from his laboratory on an antisense oligonucleotide that targets a region within the SMN2 gene called Element 1 to increase SMN protein levels made by this backup gene. This therapy works in a very similar manner to nusinersen, it just targets a different part of SMN2. The Element 1-targeting antisense drug is able to improve the survival of SMA mice. A second therapy, which uses viruses to increase the levels of a different protein called Plastin 3 (click here for more information), has been shown to improve the integrity of the connections between motor neurons and muscles (i.e. the neuromuscular junctions). Prof. Lorson showed that combining these two therapies resulted in a greater increase in muscle force and survival of SMA mice than when the drugs were tested in isolation.

Laura Torres-Benito (University of Cologne, Germany) continued highlighting the potential of combining therapies for SMA by presenting her work testing the effects on SMA mice of co-administration of two different antisense oligonucleotides. Increasing SMN levels using an antisense oligonucleotide similar to Nusinersen resulted in the previously reported improvements in the SMA model. Dr. Torres-Benito has created a second antisense oligonucleotide to reduce the levels of a different protein called NCALD. NCALD levels can modify the severity of disease in SMA patients. Reducing the amount of NCALD in SMA mice treated with the Nusinersen-like therapy resulted in a greater increase in muscle function compared with single drug treatments.

Combining therapies for SMA patients will take a great deal of further pre-clinical and clinical research; nevertheless, it is becoming increasingly evident that a multi-pronged approach to SMA treatment is very likely to lead to the best therapeutic outcome for patients. Multiple SMN-dependent strategies, such as Nusinersen and AVXS-101, could conceivably be combined to produce greater increases in SMN protein levels. These SMN-dependent treatments could also be co-administered with SMN-independent drugs that aim to support the neuromuscular system in a different way.


3. Updates on SMA clinical trials

The conference provided a nice balance between pre-clinical laboratory research and the latest findings from clinical studies. Laurent Servais (Institut de Myologie, France) and Richard Finkel (Nemours Children’s Hospital, USA) provided a great introduction to the clinical landscape in SMA, detailing the emerging symptoms of patients in response to Nusinersen, discussing clinical trial readiness and the pathway to drug discovery, and highlighting the importance of understanding the exact clinical consequences of reduced SMN levels in SMA patients, amongst other things. This provided a useful backdrop to a number of insightful presentations on the positive impact that several therapies are having for SMA patients.

Karolina Aragon-Gawinska (Institut de Myologie, France) provided data from a 10 month follow-up study on the clinical effects of Nusinersen injections in SMA Type 1 patients older than seven months. The reason for looking into this patient population is that only patients younger than seven months were included in the Biogen-led clinical trials with Type 1 infants. Since December 2016, Dr. Aragon-Gawinksa and colleagues have treated over 50 SMA Type 1 patients older than seven months, including 39 with more than six months of follow-up study. Patients were examined and muscle function assessed by the Hammersmith Infant Neurological Examination (HINE) motor scale.

On average, the median HINE score was shown to increase from 1 to 3 for patients with two copies of SMN2 and from 2 to 4 for patients with three SMN2 copies. In general, treatment resulted in stronger grasp, better cough, and improved sleep and ability to eat. Overall, the study indicates that the data generated from the older patients are in line with the data obtained in younger patients from the ENDEAR Phase 3 clinical trial. More, long-term data are required to determine the benefit and cost-effectiveness of the treatment in this patient population.

Giovanna Baranello (Carlo Besta Neurological Research Institute, Italy) provided an update from the FIREFISH Phase 2 clinical trial of the splice-modifying drug RG7916 (click here for further information). RG7916 is a small molecule, oral drug that targets and encourages the SMN2 backup gene to produce more functional SMN protein. The trial is open label (meaning that there is no placebo group) and is being conducted in the US, Belgium, Italy, Switzerland, and Turkey. RG7916 will be administered to approximately 50 infants with SMA Type 1 (aged 1-7 months who have two copies of the SMN2 gene). Principally designed to test the safety, tolerability, and properties of the drug, FIREFISH is divided into two parts: over the first four weeks, Part 1 aims to find a safe and tolerable dose of RG7916, which will then be tested in the second part of the trial over 24 months.

Data presented by Dr. Baranello indicate that RG7916 continues to be safe and well tolerated and that there have been no drug-related safety events leading to patient withdrawal from the trial. A total of 16 patients have thus far been enrolled in Part 1 of the study, with treatment occurring between 3-7 months of age. No patient on the drug has yet lost the ability to swallow or required tracheostomy or permanent ventilation. The presentation was concluded with the update that Part 2 of the FIREFISH trial is expected to start in the first quarter of 2018.

Further information

Francesco Muntoni (University College London, UK) concluded an excellent conference with a presentation on the long-term, open-label, follow-up study of the neuro-protective drug Olesoxime (click here for more information). A Phase 2 clinical trial of Olexosime in type 2 and non-ambulatory Type 3 SMA patients previously provided evidence that Olesoxime treatment resulted in maintenance of patient muscle function over the course of the two year study (click here for more information).

The latest study of Olesoxime, named OLEOS, is an extension of the previous trial (conducted from 2010 to 2013), and has enrolled only those patients involved in the initial trial (78% patient retention between the trials). Consequently, there was a three year discontinuation of the drug in these patients, as OLEOS started in 2016. Unfortunately, the motor function of patients had declined between the end of the first trial and the start of OLEOS. Nevertheless, Prof. Muntoni provided evidence that patient motor function stabilised once again with Olesoxime treatment over the 12 month period of the OLEOS trial. These data indicate that Olesoxime can prevent loss of motor function, and that this can occur at different stages of SMA. The pharmaceutical company Roche are currently deciding how to take Olesoxime forward for SMA patients.