Research / Updates

SMA Research

The Ohio State University is part of a collaborative multi-center effort called Project Cure SMA designed to help find a treatment/therapies for those with SMA. Please contact Sharon Chelnick for more information or to sign up for a trial at columbus@projectcuresma.org. For a complete update on the most current clinical trials at OSU and other participating centers involved in Project Cure SMA visit Project Cure SMA.

Update: February 4, 2010

According to Dr. Kaspar, Principal Investigator, The Research Institute at Nationwide Children's Hospital: Based on positive pre-clinical studies using a gene therapy to treat a mouse mouse model of SMA, The Kaspar and Burghes Laboratories at Nationwide Children's Hospital and The Ohio State University initiated preliminary studies in non-human primates and have seen successful translation of the gene delivery approach in a larger species. These results have prompted a research and clinical team including Dr. Kissel, Dr. Kolb, and Dr. Mendell to be established to initiate a translational program for human clinical trials for SMA. Presentation of the data and the plans to rapidly move the program forward are forthcoming in the next several weeks. More info coming soon.

Update: August 27, 2009

Breakthrough in the study of central nervous systems: Investigators at The Research Institute at Nationwide Children's Hospital have identified a non-invasive method for delivering genes to the central nervous system, a strategy that penetrates the body's protective blood-brain barrier with unprecedented success. To read more about the research breakthrough visit our research articles page.

Update: October 1, 2008

Greetings SMA families, researchers and friends: We would like to extend our deepest thanks for your dedication and all you have done to help grow support for the SMA Treatment Acceleration Act (H.R. 3334/S. 2042). Thanks to your efforts, 83 Members of the House of Representatives and 21 Senators have signed on to the bill, a major milestone for the first-ever federal legislation authorizing SMA funding.

Our approach and goals for the rest of this year are to continue to push for consideration of the bill. Congress is likely to recess for the fall election season as early as this week, but, there is a possibility that a “lame duck” session will occur following the November elections and before the new Congress and President are sworn into office. If Congress does return for a lame duck session, it is possible that the SMA Treatment Acceleration Act could be considered. As part of an effort to create such an opportunity, our government relations team is in ongoing discussions with Congressional leadership and senior members of the House Energy and Commerce Committee on both sides of the aisle.

Regardless of the outcome of a lame duck session, we have made extraordinary progress over the past 12 months which positions us perfectly to reintroduce the bill at the start of the new Congress next January, continue to grow support, and work towards passage and enactment. Thank you again for your continued hard work as we make progress in securing support for our Act. As we continue our discussions with Congressional leaders in the coming months, we will provide additional updates as well as calls to action to seek your help in moving key decision makers in the House and Senate.

NOTE: If you have any questions about the SMA Treatment Acceleration Act, please feel free to contact any one of our Government Affairs staff: Laura Breiteneicher of the SMA Foundation (laurab@wswdc.com / 202-589-0800), Spencer Perlman of Families of SMA (spencer@fsma.org / 202-333-5750), or Caroline Gibson of Fight SMA (carolinegibson@fightsma.com / 804-515-0080).

Update: August 28, 2008

Embryonic motor axon development in the severe SMA mouse: Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein. Previously, cultured SMA motor neurons showed reduced growth cone size and axonal length. Furthermore, reduction of SMN in zebrafish resulted in truncation followed by branching of motor neuron axons. In this study, motor neurons labeled with green fluorescent protein (GFP) were examined in SMA mice from embryonic day 10.5 to postnatal day 2. SMA motor axons showed no defect in axonal formation or outgrowth at any stage of development. However, a significant increase in synapses lacking motor axon input was detected in embryonic SMA mice. Therefore, one of the earliest detectable morphological defects in the SMA mice is the loss of synapse occupation by motor axons. This indicates that in severe SMA mice there are no defects in motor axon formation however, we find evidence of denervation in embryogenesis.

Read the complete study at Oxford Journals

Vicki L. McGovern1, Tatiana O. Gavrilina1,2, Christine E. Beattie3 and Arthur H.M. Burghes1*
1 Department of Molecular and Cellular Biochemistry 2 Department of Neurology 3 Department of Neuroscience and Center for Molecular Neurobiology, The Ohio State University, Columbus, OH 43210, USA.
* To whom correspondence should be addressed at: Department of Molecular and Cellular Biochemistry, The Ohio State University, 363 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA. Tel: +1 6146884759; Fax: +1 6142924118; Email: burghes.1@osu.edu
Received May 16, 2008; Accepted July 1, 2008

Update: July 9, 2008

The Ohio State University Medical Center, Department of Neurology is currently enrolling infants with type 1 SMA for the evaluation of Valproic Acid and Carnitine as a potential treatment for SMA. This is a multi center trial fully funded by Families of SMA. For more information on this trial at OSU please contact Shelli Farley at Shelli.Farley@NationwideChildrens.org or call 614-722-2654.

To find other locations for this clinical trial or for more information please visit FSMA. A list of ALL ongoing SMA Clinical Trials can be found at ClinicalTrials.gov.

Update: April 2, 2008

The Kaspar Laboratory at The Research Institute at Nationwide Children's Hospital has an SMA research program that is focusing on therapy development along with basic science studies to understand this disease. The laboratory has specific expertise in gene therapy and stem cell biology. Researchers in the laboratory are currently developing a novel gene therapy that specifically targets motor neurons to replace the gene diminished in SMA. Initial results have demonstrated that we are able to target motor neurons throughout the entire spinal cord efficiently with a one-time dosing, which is the first study to demonstrate this. Current studies are focused on testing this approach in mouse models of SMA. Furthermore, the laboratory has exciting results on defining stem cells, of various types and sources to be directed to differentiate into motor neurons. New studies are being performed to investigate the ability for these cells to regenerate lost motor neurons along with modeling various types of SMA. The laboratory is part of the Center for Gene Therapy and is a translational laboratory that will be able to perform clinical studies using gene therapy vectors by the construction of a new Current Good Manufacturing Practice facility (c-GMP) which is currently in progress. This facility will meet the FDA’s guidelines for production of sterile drug products, allowing our center to produce drug products on-site that are safe enough for human injection.

Update: June 22, 2007

deCODE Chemistry, Inc. and Families of SMA announce the selection of the first ever novel SMA drug compound targeted specifically to treat SMA. Upon gaining FDA approval, the HOPE is to begin clinical trials with this new "Clinical Candidate" within one year. Read the full story

"The SMA Treatment Acceleration Act" will be introduced in the U.S. House of Representatives and the U.S. Senate very soon. The proposed legislation was developed through a collaborative effort among the SMA Foundation, Families of SMA and FightSMA. YOU can help continue their efforts when we announce a "National Call To Action" as soon as the bill is formerly introduced. We will be asking YOU to contact your members of Congress to ask them to join our fight by cosponsoring this bill. More details on the Acceleration Act

Update: April 2007

Carl Reed visits Washington D.C. and makes his way to Capitol Hill visiting with our members of congress and our senator to introduce and encourage their support of the SMA Treatment Acceleration Act and to ask for their continued support of federal funding for SMA. More info on the FightSMA Annual Conference 2007 and SMA Day on Capitol Hill.

From left to right: Congressman David Hobson, Carl Reed, Archie Griffin, and Congressman Pat Tiberi

Update: June 6, 2007

The Ohio State University begins the first clinical drug trial for adults with SMA called THE VALIANT SMA STUDY. For more information and how to enroll, go to Project Cure.

Clinical Trial transcript from the live chat with Dr. John Kissel

2006 SMA Update by Dr. Arthur Burghes

Introduction: Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron 1 gene (SMN1) and retention of SMN2. The SMN1 gene produces more SMN protein than SMN2 and thus there is insufficient SMN for motor neurons when SMN1 is absent, this causes SMA. The first question that comes to mind is can SMN2 produce the right type of SMN? The answer to this question is a clear- yes, it can. This has been shown both in mice and humans where high copy number of SMN2 corrects the phenotype. This has also enabled screens to identify compounds that could stimulate SMN2 to produce more SMN. Yes-compounds have been identified which do stimulate SMN2 in a test situation. But whether they work to stimulate SMN2 in a whole animal or when they have to be given to modify a SMA phenotype has not been determined. There remains in SMA a series of questions some at the basic level and some at the translation, of basic findings into treatment. Our efforts over the past two years have been directed at, answering some of these questions. In so doing we have brought in new investigators at Ohio State and made the foundation of a Motor Neuron Center at the fore front of motor neuron research.

Groups currently in Spinal Muscular Atrophy research at Ohio State and current research areas:

  • Arthur Burghes Development of SMA mice, Developing and testing drugs using these mice. Determining when and where high levels of SMN are required to correct SMA and understanding how low levels of SMN cause SMA
  • Christine Beattie: Development of SMA fish. Using fish to test drug compounds. Testing which forms of SMN suppress the fish phenotype and what complex is critical for development of SMA.
  • John Kissel: Clinical Trials in SMA and characterization of biomarkers for clinical trials.
  • Tom Prior: Developed SMA carrier test. Testing for SMA and carrier status. Development of newborn screens. At Columbus Children’s Hospital
  • Dawn Chandler: Analysis of SMN2 splicing and factors affecting it, Timing of therapeutic intervention. Reagent sharing

In addition to our own research at OSU we have stimulated many groups to enter the SMA field providing reagents and techniques. The SMA mice developed at OSU are now distributed by Jackson and readily available to all. In addition the fish model developed by Dr Beattie’s laboratory is being used by laboratories all around the world to understand the fundamentals of SMA. Apart from these reagents we have provided many others to laboratories throughout the world. We have also shared our drug delivery methods( developed by Matthew Butchbach) with Psycho Genics prior to publication to allow rapid development of testing compounds in SMA mice.

Understanding SMNs function in relation to SMA

Much has been reported about the functions of SMN. However very little of this information clearly relates to how reduction of SMN causes SMA. As diagramed above, a major question is whether SMN in the nucleus or axon is critical for SMA. SMN is found in the nucleus in structures called gems and is known to be important in the formation of a particular type of RNA/ protein complex called snRNPs. However, SMN is also important for other RNA/protein complexes and is found in neuronal axons. So what function of SMN causes SMA; is it the axon function or the nuclear function that is critical? Some researchers believe motor neurons just require more SMN and it is this sensitivity that is the critical point. Others believe that SMN has a unique function in motor neurons which is affected when SMN levels are reduced as in SMA. SMA is caused not by a lack of SMN but by low levels of functional SMN. Indeed this often gets overlooked in that any function assigned to SMN is automatically believed to be critical in SMA. This is not true. It is possible that SMN2 could produce sufficient SMN to support one function, but not enough for a second function, which is critical in SMA. Thus, dissecting the protein to define the different functions then testing which of these are critical in SMA is crucial. These studies can be done more efficiently in animals such as the Zebrafish hence the fish model of SMA.

The Fish

Zebrafish is a vertebrate organism which has a series of advantages for studying SMA. In particular the embryo develops externally and is clear thus allowing the observation of motor neurons during development. Below results from the work of Dr. Beattie’s laboratory with the fish is shown. Note the altered motor axon pattern. In SMA the amount of SMN is reduced. This can be mimicked relatively simply in fish by knocking down the level of SMN to that seen in SMA. Interestingly, this results in a specific defect in the motor axons which can readily be observed as seen above. Defective motor axons can be rescued by adding SMN back to the fish. In addition it can be shown that only reduction of SMN in motor neurons is required to obtain this effect. This system can be used to look at other members of the SMN complex as well as what forms of SMN rescue. Using this analysis the results demonstrate that the known nuclear function of SMN is not critical for normal motor axon development. The results from this system can then be extended into mice to further ensure that the correct function of SMN is being assessed.

The Mice

The Burghes laboratory along with their collaborator the Sendtner laboratory in Germany have developed SMA mice exhibiting SMA phenotypes: severe (type1), moderate (type II) and mild (type III) SMA. These mice can be used to understand the fundamentals of the disease in a mammal. Indeed, we have shown that motor neuron loss occurs at different times in the different forms of the disease. The milder the phenotype the latter the motor neuron loss occurs. Motor neuron cultures from these mice have been developed by the Sendtner laboratory and show shorter axons than normal motor neurons in a similar manner to that reported for the fish. But does this occur in the mouse itself and not just in culture? We have started analyzing this in detail and below is shown intercostals motor neurons from mice labeled with GFP.There may be compensatory mechanisms in mammals that are lacking in other vertebrates or cultured neurons. Currently we are asking can we detect defects in mice like we do in fish and cultured motor neurons. The movement of results between different models of SMA is important in understanding the disease mechanism.

Motor neurons labeled with GFP in mice.

As mentioned above we have identified forms of SMN that do or do not correct the SMA fish. These forms of SMN are useful for dissecting the critical SMN function in SMA. We are currently testing these specific construct to answer whether they do correct SMA in mice. This will be important in being able to determining the critical molecular function of SMN that is lost in SMA. A question that may be asked is why is it important to know the basic function of SMN that when absent gives rise to SMA? The main answer I would give is it opens up novel avenues for therapeutics. For example you can restore the critical function independent of increasing SMN. This could be extremely important in both understanding SMA and developing a therapy that works. Indeed, I would compare the unraveling of the SMN function that is critical to SMA to the cloning of the SMN genes.

When and where are high levels of SMN needed? A number of drugs have been developed on the principal that increasing SMN will modify SMA. This is based in a large part on our observations that high copy number of SMN2 rescues SMA mice and patients with high copy number of SMN2 have mild or no clinical symptoms. An important piece of information that is lacking where and when, this high level of SMN is needed. To address the question of where high SMN levels are required we have created SMA mice which express SMN in particular places in the body. We first showed that the complete form of SMN rescues SMA. Some workers have reported different forms of SMN that lack one end and indicated they could be important for SMA. Our data indicate that these other SMN forms are not required to correct SMA. Second, very high levels of SMN in just muscle do not correct SMA or have any effect on the SMA phenotype in mice. In contrast, high expression at relatively early time points in neurons does rescue the SMA phenotype. Thus expression in neurons is required and critical for correction of the SMA phenotype. Thirdly, high expression of SMN in all tissues is not required. Some questions remain such as whether some expression in addition to that provided by SMN2 is required in muscle in order to get correction of SMA and whether motor neurons are the only neuron to require high SMN levels. To address this we are currently making mice which only have high expression in motor neurons. These mice have been more difficult to make but we believe they are critical for understanding SMA at a basic level and for drug development. Knowing when high levels of SMN are required in neurons is important in considering the effects of a drug in a clinical trial. It is also important for testing the drug effectively in mice. So far we have two observations in this regard. Introduction of high levels of SMN prior to embryonic day 15 corrects severe SMA mice phenotype. In mild SMA mice introduction of SMN in young postnatal mice has a positive effect. Thus introduction of high levels of SMN prior to motor neuron loss in the spinal cord does benefit SMA mice. What is currently not clear is whether introduction of SMN after motor neuron loss begins has any effect and a more exact translation of these time points into human SMA. We have, and are continuing to develop mice that have inducible SMN which can be turned off or on at specific time points. These mice have been exceptionally difficult to develop, but are very important in further refining the treatment window for SMA.

Testing and drug development in SMA

The moderate SMA mice which live on average to 14 days and were recently published in Human Molecular Genetics and have become the main stay of drug testing in SMA.. We have developed a system that allows oral drug delivery to neonatal mice as early as day 2. We are testing a whole panel of drugs through this system. In particular, we have looked at butyrate and there derivatives that give enhanced stability in animals. These molecules clearly have a beneficial effect in mice by extending survival considerably and enhancing there clinical motor function. In our analysis of this treatment no increase in SMN has been detected raising the possibility that these compounds work independent of SMN induction. We are testing a series of additional compounds in this system and this technique has been transported to other investigators prior to publication and is being used successfully. In addition to these studies it is important to continue more basic studies on drug compounds. How to compounds that induce SMN in culture work? What targets do these drugs act on? It is our goal to find compounds that alter the SMA phenotype and determine how they work this knowledge can be used to find the most effective compounds. In addition to the fundamental studies described above Dr Prior has taken the first steps towards developing an assay for detection of SMA in newborns and Dr. Kissel has been active in the SMA clinical trial of VPA. Thus the work is pushing ahead on many fronts at OSU towards effective and safe treatments for SMA. Although not mentioned by name in this article there are many people (Technicians, Graduate students, Postdoctoral researchers and Clinicians) who have or are working in the various OSU laboratories hard to move SMA research. Research together with families will move progress ahead rapidly towards the goal of safe effective treatment for SMA.

Conclusion

We believe our strength is in innovation. We have developed SMA mice and fish. We stand on the verge of truly understanding the critical function of SMN in SMA. We have drugs that do have an effect on mice. We need to optimize these drugs using basic system and test safe effective drugs in human trials. We have shipped mice, many reagents and techniques to laboratories all over the world. We believe by making all of these available to the neuroscience field that it has and will continue to have a major impact on moving SMA towards a cure. None of this work would have been possible without the Miracle For Madison Fund and several other family funds supporting SMA research at OSU. We attempt to use the Miracle For Madison Fund to pioneer work that is highly innovative and therefore risky. This type of research, is not funded by NIH, but when we are successful and show that it works, we can then apply for additional grant funding which is indeed moving SMA forward.

A Cure Within Reach

A cure is within reach, thanks to the many breakthroughs from these and many other researchers around the world. MFM&F believes the best hope to finding a cure for children and adults suffering from SMA, lies in the commitment of funds toward this research.