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. "

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So, the research team went on to compare the new normalized scores to a measure of adaptive behavior and a biological measure of the severity of fragile X syndrome. Without a normal copy of the fragile X gene, a vital protein (FMR1 protein, or FMRP) is not made and the result is the onset of characteristic mental disorders, which can range from learning disabilities to severe cognitive or intellectual disabilities, such as autism.

Hessl and his colleagues compared the levels of FMRP in blood from the test subjects to their new scores and found a significant correlation. They found similarly significant correlations between the IQ test scores and scores on the Vineland Adaptive Behavior Composite, which measures personal and social skills used in everyday living.

Treatment of fragile X syndrome depends on its manifestations in the individual, and range from behavioral therapy to medication. Widespread use of new normalized scores would allow physicians to better treat their patients, Hessl said.

Psychological Corporation, the publishers of the Wexler IQ test, gave permission for their raw date to be used in the context of research.

"I think we've made a good case for the makers of this test and others to release raw data to researchers so that this method can be applied to other populations with intellectual disabilities," Hessl said.

He is also hopeful that someday soon he will get permission to use his new scoring method when treating his patients. In the future, the publishers of IQ tests should include lower-functioning individuals in their standardization studies, Hessl said.

"This might mean over-sampling those with intellectual disability in order to get more sensitivity, but it would help so many children," he said.

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