We will be posting a series of summaries from our 2015 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This update covers a session on SMN Partners and Therapeutic Targets. The session was moderated by Arthur Burghes, MD, PhD.
SMN Partners and Candidate Therapeutic Targets, Part 1
Individuals with SMA do not correctly produce survival motor neuron (SMN) protein at high enough levels, due to a genetic mutation in the SMN1 gene. Over the preceding several years, we have become increasingly excited about the potential to restore SMN expression. This could be done by prompting the low-functioning SMN2 gene (the SMA “backup gene”) to make more protein, or by replacing SMN directly using, for example, gene therapy. Indeed, therapies targeted at restoring SMN levels are currently in clinical trials. However, there may be ways to treat SMA that do not involve increasing SMN levels. Drugs targeting alternative pathways should be able to be used in combination with SMN enhancing therapies.
Researchers believe that there are a number of different cellular pathways and molecules that could be targeted by drugs to restore SMN expression. These could be used in combination with each other. Some of the most pressing current issues in this area include: discovering the cellular targets of current drug candidates that increase SMN. This knowledge can be utilized in make new, second generation drugs against these cellular targets once identified.
- Discovering non-SMN based targets, which suppress a biological process that is affected in SMA, such as the death of the motor neuron through neuroprotection or the strength of muscle with low motor neuron input is important too. These might be effective in older patients later in older stages of the disease and can be used in combination with SMN enhancing therapies.
- Discovering the molecules that are disrupted due to low SMN levels could provide a way to by-pass the need for SMN all together. Correcting them to normal state might help at latter stages of the disease, as well as give greater insight into the pathways that cause SMA.
The session on SMN Partners and Therapeutic Candidates explored the specific molecules that could possibly be candidates for such alternatives therapies in SMA.
Roche/PTC have identified a molecule that increases the incorporation of SMN2 exon 7, resulting in more SMN protein from the SMN2 gene. These drug compounds have a large impact in SMA mice, and they have moved into clinical trials. The first presentation was by Dr. Sivaramakrishan at Roche on identifying the target of the Roche/PTC compound and exactly how it acts on the SMN2 RNA to increase SMN levels. This is important knowledge since the drug target can be used to guide further development of the drug and well as do drugs that do this act better..
A critical question that arose from this talk is whether this drug works the same way as the Novartis compound currently being tested in clinical trials. If these two drugs work through different mechanisms, this would provide further opportunity for either combining these drugs for therapeutic use or developing second generation drugs targeting these molecules.
The second talk was given by Dr. Kye from Boston Children’s Hospital and University of Cologne on work funded by Cure SMA that concerns alteration of micro RNA183, another possible target of low SMN. It appears to have altered abundance when SMN levels are low. The increase of micro RNA183 results in decreased activity of a cellular pathway called mTOR. Blocking of this micro RNA resulted in restoration of the mTOR activity in SMA cells. The decreased activity of mTOR could contribute to the SMA pathology and offer a new target for therapeutic intervention. The next important question to be asked is how effective is alteration of the mTOR pathway is in modulating SMA. This remains unclear at the present time, but can be tested in mouse models of SMA.
The third talk was given by Dr. Groen from University of Edinburgh, who presented data concerning a protein called UBA1. SMN deficiency leads to reduced UBA1 activity. It has been suggested by authors that UBA1 plays an important role in the generation of the SMA phenotype. Currently, it is not understood how deficiency of SMN might lead to alterations in UBA1. However, interestingly, iPS cells derived motor neurons from SMA patients (fibroblasts cells that from skin can be converted to stem cells that can then be coaxed into motor neuron cells) also show reduced UBA1 activity.
The forth talk was given by Dr. Gangwani at Texas Tech University. Dr. Gangwani and his group have identified that SMN deficiency in SMA leads to activation of JNK3 pathway. This cellular pathway has been implicated to be altered in a number of neurological disorders, like Alzheimer’s and Parkinson’s disease. It remains to be determined exactly how SMN deficiency causes activation of JNK3 and how central its role is in the neurodegeneration phenotype..
The fifth talk concerned a specific pathway in SMA that leads to neuron death. Dr. Nimrod Miller from the Ma lab at Northwestern University/Lurie Children’s Hospital, in a project funded by Cure SMA, has found that deficiency of SMN results in increased phosphorylation (this involves placing a phosphorous group on a protein, which often determines whether a protein is in a working state or not) of the a protein called tau. Reversing this process resulted in rescue of some aspects of motor neuron biology in mouse models of SMA.
Overall, the work from this session highlighted the numerous pathways that are impacted upon SMN depletion, and that SMA pathology is a complex process. Many of these pathways might possibly be targeted for therapeutic benefit.
Pictured above: Presenter Min Kye at the podium.