COLUMBUS, Ohio - Researchers are one step closer to treating spinal muscular atrophy (SMA), the most common inherited cause of childhood mortality.
In a new study in mice, scientists found that inserting extra copies of a specific gene helped the mice produce sufficient amounts of a protein called SMN. Low amounts of this protein cause SMA. The results suggest that activating the expression of this gene may someday provide a strategy for treating human SMA patients, said Arthur Burghes, a co-author of the study and an associate professor of medical biochemistry and neurology at Ohio State.
The research appears in the February issue of the journal Human Molecular Genetics.
SMA is an autosomal recessive disorder. This means that each parent has one chromosome that lacks SMN1 and one chromosome with SMN1. Their offspring have a one-in-four chance of getting the chromosomes that lack SMN1 and developing the disease.
SMA affects 1 out of 10,000 children, causing the nerve cells in the spinal cord and brain stem to deteriorate. This degeneration is caused by an insufficient amount of survival motor neuron (SMN) protein present in the motor neurons. Two genes - SMN1 and SMN2 - manufacture SMN. While SMN1 makes enough of the protein, SMN2 does not. Without enough protein, motor neurons cannot function properly. In patients with SMA, the SMN1 gene is either missing or mutated.
But by increasing the number of copies of the SMN2 gene in mice, adequate amounts of the protein were produced, according to Burghes. The increase in SMN2 compensated for the missing SMN1 gene. Enough SMN protein was produced, and the motor neurons in the mice developed properly.
"More of the SMN2 genes - at least eight copies - seemed to compensate for the lack of SMN1 in these mice," he said. "Increasing the expression of the SMN2 gene may provide a strategy for treating patients with SMA."
Burghes and his colleagues developed two strains of mice which lacked the SMN1 gene. Mice don't normally have the SMN2 gene. The researchers developed one strain of mice that had no more than two copies of the SMN2 gene, and one strain of mice with eight to 16 copies.
The mice with one or two copies of SMN2 mimicked the low SMN protein levels found in humans with the severest form of SMA.
"At birth, these mice appeared to be genetically normal," Burghes said. "But they started to deteriorate within two to three days. They were less active and had difficulty breathing. They eventually developed tremors in their limbs, and died within four to six days after birth. This contrasts with the mice that had 8 copies of the SMN2 gene - these mice were normal."
To determine the loss of motor neurons in each strain of mice, the researchers sacrificed some of the animals between the ages of one and five days. Tissue sections of each mouse were preserved in paraffin, and motor neurons counted under a microscope.
"We found relatively normal numbers of motor neurons in the spinal cord of all the day-old mice, regardless of their respective amounts of the SMN2 gene," Burghes said. "Yet by day five, there was a dramatic loss of these cells in the mice with only one or two copies of SMN2.
"This suggests that motor neurons develop normally in SMN-deficient mice, but die in the late stages of the disease," Burghes said. Compared with a group of healthy, SMN-producing mice, the animals with few copies of the SMN2 gene produced 10 to 20 times less protein. At the conclusion of the study, two of the mice with high levels of the SMN2 gene were 10 months old, and still did not show signs of SMA.
Mice which carried high numbers of the SMN2 gene produced protein levels equivalent to the healthy mice Burghes used as controls.
"If development of the disease depends on levels of SMN protein, then it's not surprising that the mice with high levels of SMN2 are normal," Burghes said.
Researchers aren't sure why motor neurons rely on SMN. Infants born with the severest form of SMA (Type I SMA) usually develop symptoms in the first six months of life, and usually die from respiratory complications before reaching their second birthday. Babies born with the intermediate form of the disease - Type II SMA - develop symptoms by 18 months of age and never gain the ability to walk. People born with Type III SMA -- the mildest form -- can live well into adulthood, but may lose the ability to walk and often develop respiratory problems.
Funding for this study came from the Families of Spinal Muscular Atrophy (FSMA); the Preston fund; the Madison fund; the Mathew fund; the Muscular Dystrophy Association of America; the National Institutes of Health; and from the Deutsche Forschungsgemeinschaft, a German scientific research and funding agency.
Burghes co-authored the study with Umrao Monani, Daniel Coovert, Catia Andreassi, Thanh Le, all with the department of neurology at Ohio State; Michael Sendtner, Sibylle Jablonka, Berthold Schrank and Wilfred Rossol, all with the department of neurology at the University of Wuerzburg in Wuerzberg, Germany; D. William Parsons and Thomas Prior, both with the department of pathology at Ohio State; and Glenn Morris, with the MRIC Biochemistry Group at the N.E. Wales Institute in Wrexham, United Kingdom.
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