Gene swap may halt deadly childhood disorder

IOWA STATE (US)—By replacing a poor-performing gene with a healthy one, researchers may have moved one step closer to identifying a treatment for spinal muscular atrophy, the second-leading cause of infant mortality in the world.

Ravindra Singh, associate professor in biomedical sciences at Iowa State University’s College of Veterinary Medicine, is leading the research effort. He believes this technology could also work to treat other diseases.

“We know that Parkinson’s disease, Alzheimer’s disease, cystic fibrosis, multiple sclerosis, and cancer all come from genes that are aberrantly spliced,” he says. “If this is a model disease, meaning we succeed in treating spinal muscular atrophy, we will know how to correct splicing of other genes in other diseases.”

Spinal muscular atrophy affects as many as 1 in 6,000 children every year, although 1 in 40 people are carriers of the disease—they don’t have the symptoms, but could pass the disease to their children. Those born with the most severe type of spinal muscular atrophy die within two years.

About 95 percent of people with the condition have a mutated or deleted gene called survival motor neuron 1 (SMN1) that doesn’t correctly do its job of creating functional SMN proteins, which provide protection from spinal muscular atrophy.

There is a gene already in humans that looks very much like SMN1, so much so that it’s called SMN2. The SMN2 gene doesn’t seem to serve any function that researchers can identify.

Singh has discovered a way of using SMN2 to produce the working SMN protein. When SMN2 makes enough SMN, it compensates for the mutated or malfunctioning gene.

All proteins in human bodies are made by copying genes. This copy is called pre-mRNA, which becomes mRNA by splicing out certain parts of the sequence that are noncoding, meaning they don’t help the function of the gene.

These noncoding portions of the pre-mRNA are called intronic sequences, sometimes referred to as junk sequence because they are originally copied from junk DNA. SMN2 typically doesn’t produce normal protein because of the presence of a specific intronic sequence in the gene or DNA.

To make SMN2 behave as SMN1, Singh has introduced a small antisense oligonucleotide that blocks this specific intronic sequence. When the intronic sequence is blocked, SMN2 produces normal proteins and acts, in effect, like SMN1.

“The significance of our work is that we have this stuff called junk DNA in SMN2,” says Singh. “We found that we could get SNM2 to behave as SMN1 by introducing a small oligonucleotide. It is a very simple experiment if you think about it.”

The resulting proteins are normal just like a regular cell—free from spinal muscular atrophy.

“Our cells are healthy and survive,” he adds. “From that point of view, this is a major achievement.”

Researchers from the University of Massachusetts Medical School and the Medical College of Georgia contributed to the study, which is highlighted as the cover story on this month’s issue of the journal RNA Biology.

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