By Dr. Alex MacKenzie, Co-Chair of FightSMA’s Scientific Advisory Committee

It is with sadness we note the passing of Dr. Hung Li earlier this year. Dr. Li’s laboratory at Academia Sinica in Taiwan made a number of important and novel observations in the study of spinal muscular atrophy, all the more impressive given his was at a center with no prior record in SMA research. Dr. Li reported the first genetically and pathologically faithful murine model of severe SMA as well as the first report of treatment of these mice with an SMN2 inducing agent, butyrate. Latterly, he made the novel observation of a role for STAT5 kinase activation in the induction of SMN2, one of the first delineations of a mechanism of induction for this locus. As well he explored the role of apoptosis in SMA and reported on Valproate therapy in a small patient cohort.

In addition to his important SMA legacy, Dr. Li published widely on other issues including renal disease and novel therapies for stroke; clearly his was fertile and creative scientific mind. He was a quiet, kindly individual who reached out to a number of us with an invitation to Taiwan to visit his laboratory a number of years ago. A true pioneer in SMA research, he will be missed.

From the National Institutes of Health:

Under the Recovery Act, the NIH has established a new program entitled Research and Research Infrastructure “Grand Opportunities” hereafter called the ”GO” grants program.This new program will support projects that address large, specific biomedical and biobehavioral research endeavors that will benefit from significant 2-year funds without the expectation of continued NIH funding beyond two years.  The research supported by the ”GO” grants program should have high short-term impact, and a high likelihood of enabling growth and investment in biomedical research and development, public health, and health care delivery.

Approximately $200 million dollars will be committed to projects resulting from this request and “only applications with budgets greater than $500,000 total costs per year for a project period of two years are expected to be considered.” This request for applications is expected to be very competitive, but it is also seen as a huge opportunity that is too important for the SMA research community to pass up.

The opening date is April 27th and the application deadline is May 27th. For more information, click here.

 FB 19 [18:51m]: Play Now | Play in Popup | Download

This is part 2 of our 2009 State of the Disease Podcast for Spinal Muscular Atrophy, where we look back at the scientific advances in SMA research in 2008 and look forward to what might come in 2009.  This two-part series features the co-chairs of Fight SMA’s scientific committee, Alex MacKenzie, M.D. (Director of the Children’s Hospital of Eastern Ontario Research Institute) and Chris Lorson, Ph. D. (Assistant Professor at the University of Missouri-Columbia).

In part one Alex and Chris discussed three of the research advances they picked as being the most significant in 2008.  In this episode, they  finish that discussion by highlighting the following 2008 findings:

• Exercise promotes motor unit development and survival in mild SMA mice
• A variety of RNA-based therapeutics that are moving in vivo
• SMA Standards of Care
  

We also tackle the future … what might come in 2009 in spinal muscular atrophy research.

If you haven’t listened to part one of this two-parter, it’s strongly suggested you visit this post, and listen there first!

To listen to this episode, you can use the Flash mp3 player above, load the Fighting Back Podcast Feed into your favorite feed reader, subscribe via iTunes or other podcast directories, or simply use the download link above to load the file onto your computer.  If you have feedback, a comment or question, or are interested in having Fighting Back tell your story, please contact page! You can also leave a message in the form of a comment on this blog as well.

 FB 18 [14:02m]: Play Now | Play in Popup | Download

2008 was an important year in spinal muscular atrophy research, as scientists and doctors continued their work to find a treatment or cure for the neuromuscular disease.  This episode of Fighting Back Podcast is the first part of our yearly “look back and look forward”.  This time we look back at 2008 and look forward to 2009 with the co-chairs of Fight SMA’s scientific committee, Alex MacKenzie, M.D. (Director of the Children’s Hospital of Eastern Ontario Research Institute) and Chris Lorson, Ph. D. (Assistant Professor at the University of Missouri-Columbia).

Before the podcast recording session, Dr. MacKenzie and Dr. Lorson forwarded their lists of what they believe to be the most important scientific findings in SMA research in 2008.  In this episode, we have a spirited discussion of the first three items on the list, including what they are and why they’re important.  The advances discussed in this episode are:

• A non-SMN modifier of disease: Plastin-3 (B. Wirth)
• Muscle vs nerve SMN rescue in SMA mice (A. Burghes)
• Nutritional supplement w/ TSA significantly increases SMA mouse survival (C. Sumner)

(Note: We are efforting links for each of these. Please check back!)

In part 2 of our State of the Disease Podcast for SMA, which will be released next week, we discuss the remaining items on the list, including the role of exercise promoting motor unit survival and the groundbreaking SMA Standards of Care that were released in 2008.  Drs. Mackenzie and Lorson also discuss the important findings they they hope will happen in 2009.

To listen to this episode, you can use the Flash mp3 player above, load the Fighting Back Podcast Feed into your favorite feed reader, subscribe via iTunes or other podcast directories, or simply use the download link above to load the file onto your computer.  If you have feedback, a comment or question, or are interested in having Fighting Back tell your story, please contact page! You can also leave a message in the form of a comment on this blog as well.

From the University of Missouri News Bureau:

MU Researchers Discover Target that Could Ease Spinal Muscular Atrophy Symptoms

Jan. 7, 2009
Story Contact: Kelsey Jackson, (573) 882-8353, JacksonKN@missouri.edu

COLUMBIA, Mo. – There is no cure for spinal muscular atrophy (SMA), a genetic disorder that causes the weakening of muscles and is the leading genetic cause of infant death, but University of Missouri researchers have discovered a new therapeutic target that improves deteriorating skeletal muscle tissue caused by SMA. The new therapy enhanced muscle strength, improved gross motor skills and increased the lifespan in a SMA model.

“This therapy does not directly target the disease-causing gene; instead it targets the pathways that affect muscle maintenance and growth,” said Chris Lorson, investigator in the Christopher S. Bond Life Sciences Center and associate professor of veterinary pathobiology in the MU College of Veterinary Medicine. “We administered a particular protein, follistatin, to SMA mouse models to determine if enhanced muscle mass impacts the symptoms of SMA. After treatment, the mice had increased muscle mass, gross motor function improvement and an increase in average life span of 30 percent.”

With the therapy, MU researchers inhibited myostatin, a protein that limits muscle tissue growth. Myostatin activity can be reduced significantly by enabling several proteins that bind to myostatin, including follistatin. When myostatin is inhibited, muscle mass and strength increase.

SMA is caused by the loss of survival motor neuron-1(SMN1). Humans have a nearly identical copy gene called SMN2. Because of a single molecular difference, SMN2 alone cannot compensate for the loss of SMN1.

“While most work in the SMA field has logically focused on targeting the SMN2 gene, the results of this study suggest that skeletal muscle is a viable therapeutic target that may reduce the severity of some SMA symptoms,” said Lorson, who also is the scientific director for FightSMA, a private spinal muscular atrophy research foundation in Richmond, Va. “Because follistatin does not alter the expression level of SMN protein, the most effective treatment would combine strategies that directly address the genetic defect in SMA as well as SMN-independent strategies that enhance skeletal muscle.”

The study, “Delivery of recombinant follistatin lessens disease severity in a mouse model of Spinal Muscular Atrophy,” was published online in the December issue of Human Molecular Genetics. The research team also consisted of graduate students Frankie Rose and Virginia Mattis, and Hans Rindt, an assistant research professor. Recently, Lorson was awarded a $370,000 grant from the Muscular Dystrophy Association to continue his research on the role of muscle in SMA.

Click here for the original news release. To read the study’s abstract, click here.

A team led by University of Wisconsin-Madison researcher and 2006 FightSMA Annual Conference presenter Dr. Clive Svendsen has shown that they can create a model of spinal muscular atrophy (SMA) in a petri dish.

Building on research previously reported which allows scientists to force skin cells to act like embryonic stem cells, the team used skin cells from a boy with SMA to create SMA affected motor neurons in the laboratory. Because these motor neurons are outside of a patient, researchers expect to be able to observe the rate of motor neuron death and test interventions much easier and safer.

The team’s findings have been published by the journal Nature. The article is “Induced pluripotent stem cells from a spinal muscular atrophy patient” by Allison D. Ebert, Junying Yu, Ferrill F. Rose, Jr., Virginia B. Mattis, Christian L. Lorson, James A. Thomson and Clive N. Svendsen.

For more information, click here to read one of the many news articles on this breakthrough.

From the University of Missouri News Bureau:

Molecular Therapy for Spinal Muscular Atrophy Closer to Clinical Use
MU researcher improves efficiency of trans-splicing therapy

Dec. 15, 2008
Story Contact: Kelsey Jackson, (573) 882-8353, JacksonKN@missouri.edu

COLUMBIA, Mo. - Spinal muscular atrophy, a neurodegenerative disorder that causes the weakening of muscles, is the leading cause of infant death and occurs in 1 in 6,000 live births. While trans-splicing (a form of molecular therapy) has had impressive results as a treatment for spinal muscular atrophy in cell-based models of disease, scientists have been unable to translate the therapy to the human body. A University of Missouri researcher has developed a strategy that will enhance trans-splicing activity and bring it closer to being used in the clinical setting.

Spinal muscular atrophy is caused by the loss of survival motor neuron-1(SMN1). In humans, a nearly identical copy gene is present called SMN2. Because of a single molecular difference, SMN2 alone cannot compensate for the loss of SMN1, but it can be used as a primary target for therapeutics, including trans-splicing. Trans-splicing therapy relies on splicing, or uniting, of mutant RNA and therapeutic RNA in order to correct RNA sequence.

To improve efficiency, the researchers developed a trans-splicing system that uses a strand of RNA that can bind to a gene and inactivate it. Turning the gene “off” reduces competition at splice sites and improves the likelihood of achieving the desired results.

“The key to introducing trans-splicing in clinical settings is developing efficient trans-splicing systems,” said Chris Lorson, investigator in the Christopher S. Bond Life Sciences Center; associate professor of veterinary pathobiology in the MU College Veterinary Medicine; and scientific director for Fight SMA, a private spinal muscular atrophy research foundation in Richmond, Va. “We have found that reducing the competition between the splice sites enhances the efficiency of trans-splicing. This strategy provides insight into the trans-splicing mechanism and significantly improves trans-splicing activity in a mouse model of spinal muscular atrophy.”

The study, “Development of a Single Vector System that Enchances Trans-splicing of SMN2 Transcripts,” was published in PLoS ONE and was co-authored by Lorson; MU researchers Tristan H. Coady, Travis D. Baughan and Monir Shababi; and Genzyme Corporation neuroscience researcher Marco A. Passini.

Click here for the original news release.

This work was funded by grants from the MDA, FightSMA, and the National Institutes of Health. To read the published article mentioned in the news release, click here.

The November 25, 2008 issue of the journal Neurology has two interesting pieces about the search for a treatment for spinal muscular atrophy (SMA): one is an article and the other is an editorial about the merits of the article’s subject.

In their editorial “Linking SMN to SMA: An assay for the rescuer,” Dr. Carsten Bonnemann and Dr. Richard Finkel give an overview of the current understanding of the genetic cause of SMA and how this is being applied to the search for therapies that lessen the severity of the disease. They then point out that there needs to be a reliable way to measure the results of these therapies to verify their effectiveness. The article entitled “A two-site ELISA can quantify upregulation of SMN protein by drugs for spinal muscular atrophy” introduces a new way to do just that. According to the editorial’s authors, while the two-site ELISA needs additional validation, it “advances the prospects of drug discovery efforts and clinical trials” and “holds promise of moving the field forward toward a therapy.”

FightSMA and Dr. Finkel have worked together in the past, when Dr. Finkel was a panelist for the “Thriving with SMA” panel at the 2007 FightSMA Annual Conference and when FightSMA assisted Dr. Finkel in distributing his 2006 survey of parents of SMA children. Two of the article’s authors, Dr. Alex MacKenzie and Dr. Glenn Morris, are also connected to FightSMA. Dr. MacKenzie is co-chair of FightSMA’s Scientific Advisory Committee and Dr. Morris has received funding from FightSMA for his research into an ELISA assay for SMN.

From the Press Release:

TREAT-NMD–EMEA workshop on clinical outcome measures in SMA signals collaborative approach to future clinical trials

TREAT-NMD, an EU-funded ‘network of excellence’ that aims to accelerate cutting-edge treatments for rare inherited neuromuscular diseases, announces a successful meeting on spinal muscular atrophy (SMA) outcome measures with the European Medicines Agency (EMEA).

A TREAT-NMD-led workshop hosted at the offices of the EMEA in London helped set the collaborative agenda for future trials in SMA. Participants included 50 representatives from the neuromuscular field, including healthcare professionals, scientists, patients and pharmaceutical industry representatives. EMEA representatives included the chairs of the Human Medicinal Products, Paediatric Medicines and Orphan Drugs Committees. There was active participation from all parties. Input from the International Care Committee (ICC) for SMA ensured that there was global representation at the meeting, the outcomes of which will also be shared with the US Food and Drug Administration (FDA).

In a new development for the neuromuscular field, the workshop focused not on discussing product-specific issues but on establishing broader common ground between the regulatory authorities and those interested in running clinical trials in SMA. In order for trials to move through the approval process without delays, consensus between trial planners and regulators on endpoints and novel methodologies is essential.

The SMA community is working extensively together and the meeting demonstrated this close link as all present spoke with a united voice on the most appropriate outcome measures for particular clinical situations. The community was complimented on its proactive approach to regulatory topics, its organisation and its international teamwork in addressing clinical trial questions for SMA.

To read the full press release, click here.

A study published online October 8th by the monthly journal ACS Chemical Biology reports that scientists have made “a key advance toward developing the first effective drug treatment for spinal muscular atrophy (SMA).”

SMA is an autosomal recessive neurodegenerative disease characterized by the dramatic loss of spinal motor neurons, resulting in muscle weakness, atrophy, and in the worst cases, the loss of ability to swallow and breathe. SMA occurs when a vital gene, the “survivor motor neuron” gene or “SMN” is deleted or mutated, preventing the creation of a protein necessary for muscle strength. Even though the key SMN gene is deleted, there is a second “copy” gene (the “SMN2″ gene) that continues to produce limited quantities of the SMN protein.

After screening hundreds of thousands of compounds, researchers are looking at C5-quinazolines as a potential method of increasing the SMN2 activity and thus the protein SMA patients lack. According to Jill Jarecki, Ph.D., Research Director at Families of SMA, “the results outlined in the paper and carried out in collaboration with Families of SMA, deCODE chemistry & biostructures, Invitrogen Corporation, and Rutgers University represent a new understanding of the physiological mechanisms that can increase SMN expression and will allow us to move forward in advancing potential treatments for it.”

To read more, click here.