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SMA Support UK at the Cure SMA Conference 2015

16 September 2015

The annual Cure SMA Conference was held in Kansas City, Missouri, USA at the Westin Crown Center hotel from 18th-20th June 2015. Many families and researchers from around the world attended the meeting, which was organised into two separate programmes of talks and activities - one for families and one for researchers. Interaction between families and researchers was organised throughout the conference, with the kids very much enjoying the wheelchair racing with the researchers.

The researchers’ meeting was structured into multiple sessions focusing on topics such as preclinical therapy development, new-born screening, and clinical trials. Cure SMA has provided overviews of these individual sessions, the links for which can be found below. After that are summaries of the key presentations delivered by SMA researchers at the conference.


Further Information

Session summaries from the Cure SMA researcher meeting:

Emerging Trends in Motor Neuron Pathobiology – Doug Kerr, MD, PhD, Cure SMA Scientific Advisory Board member

Updates from Drug Programs in Clinical Trials – representatives from six of the seven programs currently in clinical trials give an update

New-born Screening for SMA – Ethics, Rationale, and Implementation – session moderated by Kathryn Swoboda, MD

Clinical Research Studies and Outcome Measures – session moderated by Thomas Crawford, MD

Preclinical and Clinical Drug Development for SMA – session moderated by Elliot Androphy, MD

SMA Pathology – session moderated by Mark Rich, MD, PhD

SMN Targets and Partners Part 1 - session moderated by Arthur Burghes, MD, PhD

SMN Targets and Partners Part 2 - session was moderated by Rashmi Kothary, PhD

Last year’s Cure SMA conference report from SMA Support UK


1. Updates on SMA Clinical Trials

There are numerous potential SMA therapies currently being tested in patient clinical trials, the progress of which we are tracking in our drug pipeline diagram (click here for more information). At SMA Support UK we keep you up to date on the latest clinical trial news as soon as the information is released:

SMA Support UK Research Pages

At the conference, pharmaceutical representatives provided the latest information on a number of drugs being tested in clinical trials for SMA. For an overview of the clinical trial process for testing potential therapies please click here .


Clinical trials of 4-aminopyridine for Type III SMA

Claudia Chiriboga (Columbia University, New York, USA) is a clinician running clinical trials to test the short and long-term effects of a drug known as 4-aminopyridine (4-AP) in adults with SMA type III.

4-AP is a drug that modifies the electrical activity of nerve cells and it is used to treat a different disease of the nervous system called multiple sclerosis. 4-AP is able to improve walking ability and reduce fatigue in multiple sclerosis patients and it does this by prolonging the time that nerves are able to conduct signals. Given its function and evidence of effectiveness in SMA animal models, 4-AP is currently being trialled to see whether it is able to improve the muscle force and function of patients with SMA type III who are able to walk.

4-AP will not cure SMA as it is not targeting the genetic cause of the disease, i.e. the low levels of survival motor neuron (SMN) protein that lead to lower motor neuron degeneration. However, it may improve the function of the remaining lower motor neurons in patients with less severe forms of the disease, and therefore provide useful improvements in muscle force.

Dr Chiriboga presented preliminary information on the short-term, but not the long-term, effects of 4-AP from the trial.

The drug was well tolerated, but unfortunately it provided relatively little functional advantage to patients compared to placebo-treated individuals. Fatigue levels and distance covered in the Six Minute Walk Test were unaffected, and there was no improvement in strength of a number of different muscles.

However, 4-AP did result in small improvements in some nerve cell electrical function, and caused an increase in arm strength.

The trial of 4-AP has been conducted over a short duration, involved only a small number of patients, and the drug dose was low. These results are therefore only preliminary and more data is needed to confirm whether 4-AP will be a useful treatment for patients with type III SMA.


Further Information

Claudia Chiriboga web page

4-AP clinical trial page


RG7800 phase I trial data

Heidemarie Kletzl (Roche, Switzerland) presented data from the Phase 1 trial of RG7800, an SMN2 splice-modifying drug able to increase the amount of full length Survival Motor Neuron (SMN) protein made by the SMN2 gene (See Figure 1 and click here for more information on splicing and SMN2).

Figure 1. RG7800 is a splice-modifying compound that is able to increase the amount of full-length SMN protein made from the SMN2 gene.

RG7800 is a small molecule drug that has been shown to significantly improve the disease symptoms in SMA model mice by increasing the availability of SMN protein. RG7800 can be taken orally, which means that it is easily taken when compared to other strategies such as spinal cord injection.

Recently RG7800 entered a Phase Ib/IIa trial named Moonfish which had to be halted due to safety concerns (click here for more information). Unfortunately, no additional insight into this difficulty was provided at the conference. Nevertheless, the latest unpublished data from the earlier Phase I trial was presented.

Single oral doses of 0.5-90.0 mg of RG7800 were given to 48 healthy male volunteers aged 23-45 years. The trial was placebo-controlled and double-blind meaning that the test subjects and trial staff were unaware if they had received the drug or a placebo.

RG7800 was shown to be safe and well tolerated at all doses tested. It lead to an increase in the amount of full length RNA produced from the SMN2 gene without affecting SMN1 gene expression (See Figure 1 and click here for more information on splicing and SMN2).

Additional important information on RG7800 was generated, including how long it takes for the drug concentration in the blood to peak and how long it remains in the body in its active form.

Data from this Phase I trial indicate that RG7800 is safe, tolerated by the human body, and able to increase the amount of available functional SMN. Once the concerns over the safety of the drug have been addressed, it will be interesting to see whether RG7800 proves to be effective at treating SMA.


Further Information

Moonfish clinical trial page

Article on the safety concerns of RG7800


Phase I trial of Avexis SMN viral gene therapy

The use of harmless viruses to increase Survival Motor Neuron (SMN) protein levels has proven to be effective at treating disease symptoms in SMA mice. These animals have low levels of the SMN protein and develop symptoms similar to severe SMA. When given to SMA mice, the viruses are able to travel around the body and produce SMN protein, replacing that which is missing due to the condition.

However, it remains to be proven whether this therapeutic option will be safe and effective for SMA patients.

Recently a phase I trial of this virus-mediated gene therapy, known as ChariSMA, was started in the USA (click here for further information). Nine children with SMA Type I aged 0-9 months have been injected with a single dose of approximately 400 trillion viral particles containing the SMN1 gene. Avexis, the company that initiated the trial, dosed the first patient on 13th May 2014 and the ninth and final patient on 16th June 2015. Each patient is being frequently assessed over the next two years.

Brian Kaspar and Jerry Mendell (The Ohio State University, Ohio, USA) provided some of the latest data that has been generated from the phase I trial.

All patients receiving the virus have severe SMA type I, deletion of both copies of the SMN1 gene, two copies of the SMN2 gene, and were younger than 9 months of age when enrolled in the study. The viruses were administered into the blood stream at two different doses in order to see whether giving more viral particles results in a greater improvement in disease symptoms.

The primary function of this phase I trial is to assess the safety of the treatment, while motor function will also be measured as a secondary measure. If proven safe, future trials will be performed that are designed to better assess the effectiveness of the treatment.

No major safety concerns, patients requiring ventilation for more than 16 hours a day, or deaths were reported. One patient in the low-dose cohort did display an immune response to the treatment and subsequently received immunosuppressive therapy.

Motor function scores have all improved during the trial, with the best response to treatment being observed in the patient treated at the youngest age (less than two months old).

These observations are very promising for the potential of viral SMN gene therapy being a viable treatment option for SMA. Although preliminary, they also suggest that the earlier that the treatment is delivered, the better the outcome for the patient. This is something that has been repeatedly observed in animal models of SMA. We look forward to the publication of the full trial results and hopefully the start of later stage trials of this possible therapy for SMA.


Further Information

Kaspar Laboratory homepage

Mendell Laboratory homepage

SMN1 gene replacement therapy


2. A novel way to speed up clinical trials in SMA

During a clinical trial, the effectiveness of a drug or treatment must often be assessed at regular intervals by trained evaluators in order to determine the outcome of the trial. This process can be time-consuming, both due to the nature of the testing and the travel distance to the test site.

These difficulties mean that patient data is collected at infrequent intervals during a trial, leading to relatively limited results on the drug. This can in turn lead to a useful drug being discarded due to the inability to prove its usefulness.

If measurements could be performed more frequently, for instance once a week, then there would be more reliable data on the effectiveness of the drug and we would therefore be able to more accurately determine drug usefulness.

It is not feasible for patients, families, and doctors to perform rigorous testing so frequently. However, Seward Rutkove (Beth Israel Deaconess Medical Center, Massachusetts, USA) has had the interesting idea of incorporating a technique known as electrical impedance myography (EIM) into the clinical trial process for neuromuscular diseases.

EIM is a non-invasive technique that can measure how well a muscle, or group of muscles, is able to conduct a small current when voltage is applied. The ability of a muscle to conduct an electrical current is affected by its composition and structure, which are often perturbed in neuromuscular diseases such as SMA. Professor Rutkove therefore hypothesised that EIM could be used to assess the progression of SMA, and also to determine whether a treatment is of benefit to patients.

EIM is relatively easy and quick to carry out and does not require a medical professional. This means that it can be performed relatively frequently, which will increase the amount of available patient data. Having more information allows for more powerful and accurate statistical testing of drug effectiveness.

Professor Rutkove provided an example of the usefulness of EIM, showing that weekly assessments of 24 patients would provide the same amount of information on drug effectiveness as testing 91 patients every two months.

Incorporating the use of EIM in clinical trials could drastically reduce clinical trial costs, while simultaneously improving the efficiency and speed of evaluating potential treatments. Further testing of EIM is required to fully appreciate its potential. Nevertheless, once the usefulness of this technique has been confirmed for SMA it is something we could see being used in SMA clinical trials in the future.


Further Information

Rutkove Laboratory homepage

New York Times article on EIM


3. Blood vessel defects in SMA

It has been known for some time now that SMA may not just affect the lower motor neurons, especially in more severe cases of the disease (click here for more information). This has consequences for the delivery of therapies with potential to treat SMA, as it is likely that the drugs will need to target numerous different cell and tissue types in order to have the greatest chance of success. It is therefore important that we understand how the low levels of SMN protein observed in SMA models and patients affect the different systems of the body.

Simon Parson (University of Aberdeen, UK) has been working for a number of years on the blood vessels (which form the vascular system) of SMA mice. Research from his laboratory has previously shown that the density and diameter of capillaries, which are the smallest blood vessels found in the body (Figure 2), are severely affected in SMA mice. This disruption of the vascular system occurs after birth and to a similar extent in a number of different muscles. As the muscles tested show different levels of lower motor neuron degeneration, this suggests that the vascular defects are primarily caused by low SMN levels and are not dependent on lower motor neuron degeneration.

Figure 2. The vasculature system. Oxygenated blood travels away from the lungs, through arteries and then arterioles, until it reaches the capillaries. Capillaries are the smallest blood vessels in the body and they allow the exchange of various useful (e.g. oxygen) and waste products (e.g. carbon dioxide) between blood and cells. Once oxygen has been delivered to the cells, deoxygenated blood can be carried back to the lungs via the heart along venules followed by veins.

In the original work it was hypothesised that these defects would affect blood flow to muscles disturbing the delivery of oxygen and therefore muscle function. However, this theory was not tested.

Professor Parson presented his latest work that makes use of a technique able to measure the functional oxygen levels in mouse tissue. He was able to show that the capillary defects observed in SMA do indeed affect how well the vascular system functions. The reduced density and diameter of muscle capillaries was shown to increase the distances required for oxygen to travel to the cells and tissues needing it, resulting in low oxygen levels.

In addition, Professor Parson presented new data indicating that the vascular system is also severely affected in the spinal cord of SMA mice. This results in a lack of oxygen being delivered to the nerve cells found within the spinal cord, such as the motor neurons.

This work indicates that defects in the vascular system of muscles and the spinal cord are a feature of SMA. These deficiencies impair the oxygenation of tissue, which has profound effects on their ability to function properly. This work highlights the importance of understanding how low levels of SMN protein affect the body as a whole, and not just the nervous system.


Further Information

Simon Parson Q & A

Parson Laboratory homepage


4. Understanding a new therapeutic target for SMA

Despite having a number of potential therapies doing well in SMA patient clinical trials, it is vital that we improve our understanding of the mechanisms underlying the disease and continue to pursue alternative therapeutic options. The more we know about how reduced SMN levels affect the human body and cause lower motor neuron degeneration, the more proteins and genes we can potentially target to alleviate symptoms.

Recently, Thomas Gillingwater and colleagues published research identifying a new therapeutic target for SMA (click here for more information). Using a number of different animal models they were able to identify an important cellular process as being impaired in SMA-affected animals.

Different cells and tissues require very exact collections of molecules (including proteins) at distinct times in order to perform vital functions. Once produced, these molecules must be constantly recycled and degraded to ensure that unwanted substances do not build up within the cells and potentially impair their function and viability.

A protein called UBA1, essential for this “housekeeping” process of molecule degradation, was consistently reduced in SMA models. This resulted in a build-up of a second molecule called beta-catenin, which was determined to be, at least partly, responsible for some of the neuromuscular symptoms reported in the disease models.

Reducing UBA1 levels was shown to cause SMA-like neuromuscular symptoms, while reducing levels of beta-catenin was able to improve the neuromuscular defects associated with low levels of SMN.


Ewout Groen (University of Edinburgh, UK) from the Gillingwater laboratory presented his latest research designed to determine the suitability of UBA1 as a novel target for potential SMA therapies.

Using induced pluripotent stem cells from SMA patients and healthy controls, Dr Groen was first able to show that human SMA motor neurons had lower levels of UBA1 than healthy motor neurons, similar to what was previously seen in the animal models.

Given that lowering UBA1 levels causes SMA-like symptoms in animal models, and that low UBA1 levels are observed in SMA patient-derived motor neurons, it was hypothesised that increasing UBA1 levels may be able to improve SMA-associated symptoms. To do this, Dr Groen is using viruses similar to those integral to the ChariSMA gene therapy used to restore SMN levels. However, instead of having the SMN1 gene packaged into the viruses, the UBA1 gene has been engineered into the viruses instead.

These UBA1-viruses were injected into SMA model mice and early signs indicate that the treatment is able to improve motor function and body weight. Furthermore, the therapy was able to improve the negative molecular events associated with low UBA1 levels, while also causing a small increase in SMN RNA and protein levels.

This work continues to show that targeting the UBA1 gene may be an alternative or complementary therapeutic strategy for alleviating symptoms associated with SMA, and we look forward to hearing about how this work develops in the near future.


Further Information

Article on the identification of UBA1 as a therapeutic target for SMA

Thomas Gillingwater Q & A

Gillingwater Laboratory homepage