The web magazine, Slate, has a thought-provoking article entitled “The Medical Revolution: Where are the cures promised by stem cells, gene therapy, and the human genome?” which addresses the difficulties of developing new therapies.

To read the article, click here.

Work in the Lorson lab at the University of Missouri, the DiDonato lab at Northwestern University, and the Kaspar lab at Nationwide Children’s Hospital have recently shown functional and developmental cardiac defects in two severe models of spinal muscular atrophy (SMA). The studies were conducted with mouse models, not SMA patients, and all three were recently published in the journal Human Molecular Genetics.

According to Dr. Chris Lorson, FightSMA’s Science Director and also an author of one of the studies, “collectively these results highlight the importance of additional tissues in SMA that may contribute to the overall pathology in SMA - most likely in more severe cases. This is especially important when developing and testing potential therapeutics in SMA models and as novel compounds progress towards the clinic.”

Click the links below to read the article abstracts:

• Lorson Lab: Cardiac defects contribute to the pathology of spinal muscular atrophy models
• DiDonato Lab: Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice
• Kaspar Lab: Early heart failure in the SMNΔ7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery

From Nationwide Children’s Hospital:

Spinal Muscular Atrophy May Also Affect the Heart

Study details new findings in mouse model of disease; highlights existing gene delivery approach that may provide therapy

Columbus, OH - 8/11/2010

Along with skeletal muscles, it may be important to monitor heart function in patients with spinal muscular atrophy (SMA). These are the findings from a study conducted by Nationwide Children’s Hospital and published online ahead of print in Human Molecular Genetics. This is the first study to report cardiac dysfunction in mouse models of SMA.

SMA is a debilitating neurological disease that leads to wasting away of muscles throughout the body. Historically, scientists and physicians believed that SMA only affected skeletal muscles; however, new data suggests that this genetic disease may also impact the heart.

“A few studies regarding SMA patients have implicated the involvement of the cardiovascular and the autonomic nervous system,” said the study’s co-author Brian Kaspar, PhD, principal investigator in the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital. “However, there have been few to no highly powered and controlled studies to determine how common these cardiovascular anomalies are in these patients.”

The reports of altered blood flow and slowed heart rate in some SMA patients prompted Kaspar’s team to examine whether a cardiac deficit is present in a mouse model of severe SMA, developed by Arthur Burghes, PhD, professor of Molecular and Cellular Biochemistry at The Ohio State University College of Medicine, which is routinely used for drug and therapeutic-based screening.

They analyzed heart structure of the SMA mice compared with normal mice, and found that there were significant structural changes occurring in the heart of the SMA mice, along with severely impaired left-ventricular function. SMA mice also had significantly lower heart rates. After examining the underlying structure of the mouse heart cells they found it similar to the cellular structure of a heart biopsy from patient with type 3 SMA.

To read the rest of the article from Nationwide Children’s Hospital, click here.

To read the abstract of the journal article, click here.

To learn more about gene therapy, click here.

To learn more about spinal muscular atrophy, click here.

Following the publication of his team’s gene therapy work with AAV-9 in spinal muscular atrophy (SMA) mouse models (Foust et al., Nature Biotechnology), Dr. Brian Kaspar participated in Nationwide Children’s Hospital’s monthly podcast about neuromuscular research. In this podcast, Dr. Kaspar spoke about a number of topics including:

• What is spinal muscular atrophy (SMA)
• The genetics of SMA
• The difficulty developing treatments for SMA
• The results AAV-9 has shown in SMA mouse models
• The need for additional studies before moving to human trials
• The next steps toward the clinic

The podcast is available by clicking here and scrolling to the May podcast. At the time of this post, there is a problem in how the podcast is available on the Nationwide Children’s Hospital website. The audio file has a comma added at the end of the file type which prevents players from recognizing file type. In order to play the podcast, simply download it to your computer, select the file name, and remove the comma. Your computer should then recognize the podcast as a MP3 file.

Recently, FightSMA launched the “Realizing the Dream” fundraising campaign which partners with the Gwendolyn Strong Foundation to advance a common goal: to bring SMA gene therapy to clinical trial. These efforts will support Dr. Kaspar and other collaborating scientists. To learn more about the gene therapy campaign and how you can get involved, click here.

In the current issue of Quest magazine, our friends at MDA discuss a recent multi-center study that suggests spinal muscular atrophy (SMA) patients who are unable to walk but are otherwise considered to have “relatively high motor function” are at a higher risk for weight gain. This is when compared to SMA patient who do walk and to SMA patients who do not walk but have a lower level of motor function. The results seem to reinforce the importance of managing nutrition in the care of SMA patients.

To read the entire article in Quest, click here. To read the abstract of the study, click here.

For more information about SMA and nutrition, check out the links below.

• “Spinal Muscular Atrophy GI and Nutrition Care” on FightSMA’s website
• “Investigating the Impact of Nutrition on SMA” from the FightSMA’s blog
• A Family Guide to the Consensus Statement for Standard of Care in Spinal Muscular Atrophy
  Published by The Patient Advisory Group of the International Coordinating Committee (ICC) for SMA Clinical Trials
• Consensus Statement for Standard of Care in Spinal Muscular Atrophy
  Prepared by the Standard of Care Committee for Spinal Muscular Atrophy, a standing committee of the International Coordinating Committee for Spinal Muscular Atrophy

On July 21, 2010, the U.S. Senate Committee on Health, Education, Labor and Pensions (HELP) heard testimony from panelists discussing Rare and Neglected Pediatric Diseases. One of these diseases was spinal muscular atrophy (SMA).

Two of the panelists were Dr. Alan Guttmacher and Mr. John F. Crowley.

Dr. Guttmacher, who is the Acting Director at the National Institute of Child Health and Human Development (NICHD), spoke on the importance of SMA and SMA research to NIH and its officials.

Mr. Crowley, CEO and Chairman of Amicus Therapeutics, spoke about patient advocacy, and the admirable work and advocacy that FightSMA has exhibited over the years.

Click here to read the transcript of Dr. Guttmacher’s testimony and here for the transcript of Mr. Crowley’s testimony. For more information about the hearing, including the testimony of other panelists and video of the hearing, click here.

Prepared by Kathryn J. Swoboda, MD
Director, Pediatric Motor Disorders Research Program, University of Utah School of Medicine

Several years ago, Chang and colleagues published the initial observation that sodium byturate appeared to improve survival and motor function in a mouse model of SMA. Spurred by these observations, Butchbach and colleagues in the Burghes laboratory at Ohio State University subsequently began to painstakingly study other butyrate derivatives. Some of these compounds, when administered early in the course of disease in the SMA animal model, significantly improved survival, but the timing of administration proved critically important. It was clear that the compounds varied in potency, and that any benefit diminished significantly if treatment intervention were delayed. However, one of these butyrate derivatives, sodium phenylbutyrate, had been in clinical use for decades in the treatment of newborn infants with urea cycle disorders. The hypothesis that this compound, given early in the course of the disease, might improve outcomes ultimately resulted in the launch of the STOP SMA study in 2006: a phase I/II open label Study of sodium phenylbutyrate in pre-symptomatic infants with Spinal Muscular Atrophy. These efforts have been generously supported by many: FightSMA, MDA, FSMA, and the Kylee Galbraith Memorial SMA Research Fund at the University of Utah, with medication graciously provided by Ucyclyd Pharma.

We completed enrollment for the STOP SMA trial in April 2010, and early results appear promising: of six infants expected to develop type I, survival and respiratory support needs are considerably improved compared to their affected siblings and symptomatic type I infants in the database, and one infant achieved independent sitting. In addition, two of six children expected to develop type II disease achieved independent walking. In addition to the improved motor outcomes, electrophysiologic data indicate that these children have less significant denervation than expected for age based on a natural history studies. However, the next few months will undoubtedly prove critical in moving this work forward to achieve the ultimate goal of this project: demonstrating the feasibility of rapid identification of newborns with SMA in order to permit early intervention for the many promising new therapies on the horizon.

Over the next year, we anticipate completion of the final dataset for the STOP SMA trial, data analysis and dissemination, development of a STOP SMA trial registry and database for prospectively identified SMA subjects, and planning for the next steps forward to identify infants via newborn screening, using a recently validated pilot newborn screening assay. For the STOP SMA protocol, we developed a proactive monitoring program with protocol-driven interventions for nutrition and respiratory care, modeled after the current cystic fibrosis clinic model. However, further pilot studies are necessary to determine how to best implement such a program in several states in anticipation of the launch of a nationwide prospective newborn follow-up program in infants diagnosed with SMA on newborn screening. Development of this database, and dissemination of best practices and proactive monitoring protocols to physicians and parents will improve the quality and length of life and the standard of care provided to children with SMA. We are extremely grateful for the additional funds provided via the Pepsi Challenge, Stop SMA and FightSMA at this crucial time to move this project forward as quickly and efficiently as possible.

Kathryn J. Swoboda, MD
Associate Professor, Neurology and Pediatrics
Diplomate, American Board of Medical Genetics
Director, Pediatric Motor Disorders Research Program
University of Utah School of Medicine

RICHMOND, VA — Richmond-based FightSMA, a nonprofit dedicated to developing a treatment for the deadly childhood crippler spinal muscular atrophy (SMA), is awarding a $250,000 research grant to Dr. Brian Kaspar, a principal investigator at Nationwide Children’s Hospital and associate professor of The Ohio State University.

The grant will support safety and toxicity studies for AAV(-9), a potential “delivery system” for gene therapy for the treatment of SMA. “Our SMA gene therapy program at Nationwide Children’s Hospital and The Ohio State University continues to show great promise for treating SMA patients,” said Dr. Kaspar. “With this award, we will be able to test our therapy for potential safety or toxicity issues and provide important information for the regulatory process as we advance our program to the clinic in a swift and safe manner. We are all very thankful for the support of FightSMA.”

The grant has been made possible by funding both from FightSMA (www.fightsma.org) and from its associated partner organization, the Gwendolyn Strong Foundation (www.gwendolynstrongfoundation.org). “We are tremendously excited about the potential for gene therapy in SMA and our continuing collaboration with the Gwendolyn Strong Foundation and the SMA Community,” said FightSMA President Martha Slay. “Gene therapy research is a marathon run, but the work of Dr. Kaspar will advance the field significantly for SMA.”

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. SMA is caused by the absence of a gene that is critical for muscle strength, the SMN (”survivor motor neuron”) gene. That gene is absent in approximately one in 30 individuals. If both a man and woman are lacking the necessary SMN gene, the chances are 25% that any of their children will manifest SMA.

An objective of gene therapy is the restoration of the missing gene through delivery systems called “vectors.” Adeno-associated virus (AAV) is considered to be an attractive candidate for the construction of vectors.

FightSMA was created in 1991 with the mission to “strategically accelerate the development of a treatment or a cure for spinal muscular atrophy.” Working with the guidance of an international Scientific Advisory Committee, FightSMA has awarded SMA research grants at more than 40 universities and research institutions in the United States, Canada, the United Kingdom, France, and Italy. FightSMA has chapters across the United States and in Canada.

For more information, contact: www.fightsma.org or 804.515.0080

Dr. Nicholas Boulis, a recipient of FightSMA funding and past presenter at FightSMA Annual Conferences (2006, 2007, 2008, and 2009), is currently part of a study examining the delivery of cell-based therapeutics to ALS patients. Dr. Boulis developed the surgical device that provides the stability needed for a needle to deliver therapeutic agents into the spinal cord.

Read the CNN article and watch the video by clicking here.

FightSMA Canada has been awarded a C$250,000 research grant from CML HealthCare of Mississauga. The Children’s Hospital of Eastern Ontario (CHEO) Foundation will match the grant, providing a total of C$500,000 to advance spinal muscular atrophy (SMA) research. The multi-year grant will support investigation into “clinic-ready agents” that can increase the presence of Survivor Motor Neuron, a protein that is essential for muscle strength and is deficient in children diagnosed with SMA.

“SMA is a devastating disease,” said CHEO research institute’s Dr. Alex MacKenzie. “It is the number-one genetic cause of death among infants.  This generous gift from CML HealthCare and the CHEO foundation will be key to moving the fight against SMA forward and will provide the thousands of children fighting this terrifying disease with hope for an effective treatment in the future,” said Dr. MacKenzie.

“CML HealthCare is excited about supporting the fight against SMA,” said Kent Nicholson, Executive Vice President and Chief Operating Officer. “We are very impressed and inspired by the determination and dedication of the researchers and families fighting SMA, and we are proud to be a part of the fight.”

“I want to express my appreciation for the support that CML HealthCare has provided and for their continued dedication in helping us find a cure for SMA,” said Tracy Lacey, President of FightSMA Canada. “CML’s efforts have made our recent research funding campaign one of the most successful that we have ever had.”

As a leading Canadian provider of diagnostic medical services, CML HealthCare is dedicated to providing patients with Care. Confidence. Comfort.™ The nearly 40-year-old company is one of largest providers of medical imaging services in North America and one of the largest community-based providers of laboratory testing services in Ontario.

“It is companies with vision, like CML HealthCare, that are truly changing our world,” said Martha Slay, President of FightSMA. “We all benefit from their generosity and from their example.”

FightSMA is an international nonprofit corporation dedicated to developing a treatment for spinal muscular atrophy (SMA). FightSMA has awarded SMA research grants to more than 40 universities and research institutions in Canada, the United States, the United Kingdom, France, and Italy.