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.