Spinal muscular atrophy (SMA), a disease in which muscle-controlling nerve cells (motor neurons) in the spinal cord are lost, is caused by a lack of full-length SMN, a protein normally produced from DNA instructions in the SMN1 gene. People with SMA lack SMN1 genes but have SMN2 genes, from which the majority of SMN protein molecules produced are relatively short compared to full-length SMN and are nonfunctional. Efforts to coax nerve cells to read SMN2 instructions as if they were SMN1 instructions are the main focus of current research in SMA.
Researchers in the laboratory of Eric Kmiec at the University of Delaware in Newark say they’ve developed a gene repair method that has the potential to improve the prognosis in SMA.
Using a molecular “bandage” called a sequence-specific oligonucleotide, the investigators changed the way cells interpreted the DNA in the SMN2 gene and made them interpret it as if it were an SMN1 gene. They published their results Feb. 15 in Experimental Cell Research.
The investigators conducted their experiments on skin cells taken from a child with type 1 SMA, the most severe form of the disease, in which a severe deficiency of full-length SMN leads to respiratory muscle weakness and early death.
They added the oligonucleotide bandage to the cells in a laboratory dish and found that they began making more full-length, functional SMN. (Elsewhere, medications are being tested that may also boost full-length protein production from SMN2 genes.)
The researchers say further studies are now under way to test this gene-repair method in cells from patients with types 2 and 3 SMA, in which SMN levels are higher than in type 1, leading to a less severe disease. They’re also exploring methods to deliver the oligonucleotides to patients’ nerve cells.
If such a treatment, which they’ve called “targeted gene alteration,” could be delivered to these cells, the authors say, it would likely improve SMN protein levels and delay muscle atrophy.
“Our initial studies in animals are consistent with the positive results we obtained in the patient’s cells,” Kmiec said. “We’re hoping to conduct more detailed animal studies in the near future.” He also noted that combining this gene repair strategy with compounds called HDAC inhibitors is a possibility.
Kmiec and colleagues are working with the biotechnnology company OrphageniX (www.orphagenix.com) in Wilmington, Del.
Treating cells taken from patients with SMA with a compound known as a sodium-hydrogen exchanger inhibitor significantly increased production of full-length SMN protein molecules from SMN2 genes.
Jan-Gowth Chang at Kaohsiung Medical University Hospital in Kaohsiung, Taiwan, and colleagues, who published their results in the January issue of Annals of Neurology, used a compound called EIPA, which increases the hydrogen ion concentration, thereby raising the acidity level, of the environment inside cells. They’re not certain whether the mechanism for the increase in full-length SMN protein production is the increase in acidity or another effect of EIPA, but they may have uncovered an important new direction in SMA research.