Trans-splicing and gene therapy

A process called trans-splicing has been shown to increase levels of a needed protein in mice with a disease resembling severe human spinal muscular atrophy, says a research team at the University of Missouri-Columbia, whose findings were published Jan. 6, 2010, in the Journal of Neuroscience.
The process, which increased lifespan in the mice, may prove to be a promising alternative to a variety of therapeutic strategies currently under investigation for SMA.
The researchers used a technique called trans-splicing, which facilitates the joining of two separate molecules, in this case the SMN2 instructions for the removal of exon 7 and new instructions that cause inclusion of exon 7.
Mice bred to have a disease resembling a severe form of SMA each received a single intracerebral (into the brain) injection of carriers called viral vectors, containing short strands of corrective genetic instructions. Analysis revealed increased levels of full-length SMN in the mice, with trans-splicing detectable in the central nervous system, the kidney and liver and, to a lesser degree, in skeletal muscle.

Mice that received the trans-splicing treatment developed less severe symptoms than untreated mice. They lived an average of seven days, significantly longer than the untreated group, whose life span averaged less than five days.
Christian Lorson of the University of Missouri-Columbia, a study team member, noted: “The findings shed light on an additional strategy among several already under investigation for the treatment of SMA. The more options one has for treatment, the better the likelihood of finding one closely tailored to one's specific needs”. "Right now it's a good idea to put as many shots on goal as possible," Lorson said, "and clearly there are advantages and disadvantages to each approach".

Gene therapy as possibile treatment for SMA is also proposed in a study financed by Telethon and published in the scientific journal EMBO ("The splicing regulator Sam68 binds to a novel exonic splicing silencer and functions in SMN2 alternative splicing in Spinal Muscular Atrophy") by Claudio Sette, professor at the Department of Public Health and Cell Biology, University "Tor Vergata" of Rome, who also directs a research group at the IRCCS Fondazione Santa Lucia.
The research team of Claudio Sette is trying to see if they can treat SMA by making more stable the backup gene SMN2 already present in the body rather than providing a correct copy of the missing gene. What makes the protein SMN2 unstable is the lack of a portion of information that resides in the gene, which is removed during a crucial stage of its production, called splicing. Studying the molecular details of the splicing of the SMN2 gene, the team of Claudio Sette identified a new protein involved in this complex cellular phenomenon, called Sam68.
Subsequently, researchers have provided cells of patients with SMA, using a viral vector, a protein Sam68 antagonist, that blocks the defective splicing. Thus transformed, the cells produced sufficient amounts of protein SMN2 full and stable. Encouraged by these results obtained on patients' cells, the researchers will try to verify the effectiveness of this strategy in animal models of disease, making it suitable for application in humans.

(sources: MDA, Telethon)