This month, the journal Human Molecular Genetics published a special issue focused on advancements in neurological and neurodegenerative diseases. Included in this issue is an article by FightSMA’s Science Director Dr. Chris Lorson and colleagues from his lab at the University of Missouri entitled “Spinal muscular atrophy: mechanisms and therapeutic strategies.”

The abstract:

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and a leading genetic cause of infantile mortality. SMA is caused by mutation or deletion of Survival Motor Neuron-1 (SMN1). The clinical features of the disease are caused by specific degeneration of α-motor neurons in the spinal cord, leading to muscle weakness, atrophy and, in the majority of cases, premature death. A highly homologous copy gene (SMN2) is retained in almost all SMA patients but fails to generate adequate levels of SMN protein due to its defective splicing pattern. The severity of the SMA phenotype is inversely correlated with SMN2 copy number and the level of full-length SMN protein produced by SMN2 (~10–15% compared with SMN1). The natural history of SMA has been altered over the past several decades, primarily through supportive care measures, but an effective treatment does not presently exist. However, the common genetic etiology and recent progress in pre-clinical models suggest that SMA is well-suited for the development of therapeutic regimens. We summarize recent advances in translational research that hold promise for the progression towards clinical trials.

For more information, click here.

As she approaches the end of high school, Courtney Griffin is looking toward the next stage of her education: college. Like many students her age, she is touring universities, but unlike most, Courtney also has to consider accessibility and other factors because she has spinal muscular atrophy (SMA) type 3.

Recently, Courtney and her parents Terry and Deanna visited the University of Missouri, aka “Mizzou,” which is also the home-base of Dr. Chris Lorson, FightSMA’s Science Director. Dr. Lorson met with the Griffin Family and gave them a tour of his lab.

The Griffins sent this recap:

Our heartfelt thanks to Dr. Lorson for meeting with us and playing “Tour Guide Extraordinaire” at University of Missouri when we visited! We were in Columbia as an opportunity for Courtney to visit Mizzou’s gorgeous campus as part of her college search. Dr. Lorson showed us around the lab and introduced us to the many dedicated people working hard on the various SMA projects there.

We got a chuckle out of the fact that in his younger days, he used to play some hard-fought games of Ultimate Frisbee on the very spot where the Bond Life Sciences Center now stands - and where SMA research is progressing in earnest!

We had an incredibly productive day at Mizzou and we found an institution highly dedicated to accessibility, education, and research.

Thanks again Dr. Lorson!

Terry, Deanna, and Courtney Griffin

Gabriella Garbero is an 18-year-old student at the University of Missouri. Like many freshman, she took part in rush which culminated in accepting a bid from the Kappa Kappa Gamma sorority. But with this experience, Gabriella made history at MU by becoming “the first woman in the university’s history to participate fully in rush while using a wheelchair.”

Gabriella has type 2 spinal muscular atrophy. To enter sorority houses during rush, a friend set up portable ramps so Gabriella could maneuver her wheelchair over stairs. Now that she is a Kappa Kappa Gamma sister, Gabriella keeps two temporary ramps at the house, which the sorority says will be replaced by permanent ramps. Despite these improvements to the house, Gabriella will not be able to live there due to additional accessibility limitations and her dependency on additional personal aides.

With the thousands of students with disabilities on campus, Gabriella does think it is strange that she is the first to pass this milestone. But, she does give her family credit for her decision to rush, saying “I was blessed to be raised in a family where I wasn’t limited just from being in a wheelchair.” Gabriella has already inspired others to follow in her path, as her roommate, who also uses a wheelchair, is considering the next rush season.

To read the full article from the Columbia Missourian, click here.

Mike Bush, news anchor for KSDK’s NewsChannel 5 in St. Louis, did a piece about a recent show at the Touhill Peforming Arts Center at the University of Missouri-St. Louis. But, being a musical version of a classic Mark Twain novel is not what made “The Adventures of Tom Sawyer, the Musical” extraordinary. This show was put on by the Variety Children’s Theater which provides children and teens with disabilities the opportunity to work alongside professionals in all parts of the production, including on-stage performance, costume design, set design, stage management, etc.

One of the children spotlighted in Bush’s report is Kaci Conley, a ten year old with spinal muscular atrophy (SMA). When she was born, Kaci’s parents were told she wouldn’t even speak. Through hard work she has proved the prediction wrong, winning the role of Penny Temple in the musical and singing and dancing with all the other actors.

To read the full article or watch the video of the news report, click here.

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.

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.

FightSMA’s science director, Dr. Chris Lorson, is profiled in the Winter 2008 issue of the University of Missouri’s newsletter For All We Call Mizzou.

From the article, “Leading the fight against a killer of infants”:

Although many people have never heard of it, spinal muscular atrophy (SMA) is the leading genetic cause of death among infants. The neurodegenerative disease does not discriminate; it affects all ethnic groups and occurs in approximately one in 6,000 live births.

“It’s a remarkably common ‘rare’ disease,” says Chris Lorson, associate professor of veterinary pathobiology. “Most kids who develop the disease live two to five years. Treatments have been developed to extend that lifespan, but there is still no cure.”

Lorson, PhD ’97, a researcher in the Christopher S. Bond Life Sciences Center, is leading the national effort to change that. With joint appointments in the College of Veterinary Medicine and the School of Medicine, Lorson has been collaborating with researchers on campus and across the country to learn more about what causes the disease and what can be done to stop it.

“The genetics are very clear,” Lorson says. “A single gene is responsible for all clinical forms of the disease, and about 1 in 35 people carries the gene.”

When it functions normally, this particular gene, known as survival motor neuron 1 (SMN1) creates a protein necessary for motor neuron activity. Children born with a defective SMN1 gene suffer from neurodegeneration, which leads to severe muscle weakness and difficulty crawling, walking, controlling their head and neck, swallowing and even breathing.

Lorson, who is also scientific director for the nonprofit organization Fight SMA, says his team is working on a multifaceted approach that includes drug development, supportive care and a gene therapy program to replace the defective gene. Their work could offer insights into treating other diseases such as Parkinson’s, Alzheimer’s and muscular dystrophy.

“SMA represents an outstanding platform for modeling neurodegenerative disorders,” Lorson says. “It is truly an exciting time to be working in this area. Obtaining funding, however, has become a full-time job.”

To read the original article, click here.

Spinal muscular atrophy (SMA) researchers Tristan Coady and Travis Baughan, from FightSMA Science Director Dr. Chris Lorson’s laboratory at the University of Missouri, will attend and present their studies at the American Society of Gene Therapy (ASGT) Meeting in Seattle, May 30th – June 3rd.

At this year’s ASGT meeting Travis will present, “Modulating SMN2 pre-mRNA splicing: Identification of optimal targets for bi-functional RNAs.” Travis has developed second generation bi-functional RNAs that target repressor elements within SMN2 while recruiting positive factors to facilitate exon7 inclusion. Bi-functional RNAs have two functional domains, one that is a RNA sequence complimentary to the target RNA (in this case SMN2) and another that serves as a binding substrate for splicing factors which in turn promote full-length SMN expression. The original observations concerning the successful application of first generation bi-functional RNAs to alter SMN2 splicing and promote increased inclusion of exon7 were reported in the journal Molecular Therapy, 2006. The current goal of these studies is to validate the effectiveness of bi-functional RNAs in mouse models of SMA. The successful application of this technology in SMA to promote inclusion of SMN2 exon7 can be easily adapted to other diseases that are a result of aberrant pre-mRNA splicing.

Another therapeutic approach being investigated by Tristan Coady is the application of trans-splicing. Trans-splicing relies upon pre-mRNA splicing occurring between two different molecules; the endogenous RNA (for example SMN2) and the therapeutic RNA. The therapeutic RNA used in these studies contains SMN1 exon7 which when trans-spliced will form an mRNA with exons1-6 of SMN2 and exon7 of SMN1. Tristan’s studies have successfully identified trans-splicing RNAs that increase expression of full-length SMN and produce elevated levels of SMN in SMA patient fibroblasts. These studies are currently in press in the journal Molecular Therapy. The functionality of these trans-spliced RNAs is currently being tested in both tissue culture and mouse models. Tristan will present a podium presentation at the ASGT meeting entitled, “SMA Based Therapeutic Trans-Splicing RNAs Repair SMN1 Deficiency.”

FightSMA is a proud sponsor of the 10th Annual ASGT Meeting and will also be present in the Exhibit Hall at booth 324. Visitors to the booth can receive information about FightSMA research funding opportunities and can meet FightSMA scientific representatives Dr. Chris Lorson and Dr. Monique Lorson, both of the University of Missouri.