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 email@example.com. 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: November 2014
Phase 1 Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 and the
Nationwide Children's Hospital Center for Gene
Update: February 2012
Dr. Arthur Burghes discusses antisense oligomer treatment in an
SMA mouse model in February, 2012. This
article contains the transcript as well as a link to the podcast.
Update: January 20, 2012
Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis
of >72,400 specimens, the full article, from
www.PubMed.gov. The abstract is included below.
Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000
live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American
College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to
facilitate informed reproductive options, although other organizations have cited the need for additional large-scale
studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis
(n = 121) for this condition. Our analysis of large-scale population carrier screening data (n = 68,471) demonstrates
the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of
accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier
frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be
1/11,000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from
1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This
collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier
screening and prenatal diagnosis for 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
(firstname.lastname@example.org / 202-589-0800), Spencer Perlman of Families of SMA
(email@example.com / 202-333-5750), or Caroline Gibson of Fight SMA
(firstname.lastname@example.org / 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;
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
A list of ALL ongoing SMA Clinical Trials can be found at
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
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.
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 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.
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.