SMA Therapeutics: Changing the Code

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 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 (SMA), 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. (See In Focus: Spinal Muscular Atrophy.)

About SMA molecular mechanisms

SMA is the result of a deficiency of a protein called SMN, which stands for “survival of motor neurons.” SMN deficiency is caused by a mutation in the SMN1 gene that prevents full-length functional SMN from being made.

Both the SMN1 and SMN2 genes carry instructions for making SMN protein. However, the SMN2 gene’s instructions typically result in a nonfunctional version of SMN. This is because the SMN2 gene’s splicing instructions cut out a critical stretch of genetic code known as exon 7. Without exon 7, the protein made from SMN2’s genetic instructions is shortened, unstable and nonfunctional.

However, if SMN2 splicing patterns are modified, the full-length, functional SMN protein can be produced from the SMN2 gene, even if the SMN1 gene is flawed.

About the new findings

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.

Although MDA did not fund this project, study team member Christian Lorson at the University of Missouri-Columbia is a member of MDA’s Scientific Advisory Committee and is a current MDA grantee for SMA research unrelated to this study.

Meaning for patients

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."