March 19, 2008

Gene Repair Strategy Explored 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 spinal muscular atrophy (SMA), a disease in which muscle-controlling nerve cells (motor neurons) are lost and muscles become weak and atrophied.

Using a molecular “bandage” called a sequence-specific oligonucleotide, the investigators changed the DNA in a SMN2 gene so that it closely resembled the DNA in a SMN1 gene. They published their results Feb. 15 in Experimental Cell Research.

In SMA, the SMN1 gene is lost, but the SMN2 gene is retained. A protein called SMN (survival of motor neurons) is normally made from the SMN1 gene’s instructions, while a shorter, nonfunctional version of the SMN protein is made from the SMN2 gene. Converting SMN2 genes to SMN1 genes would probably be an effective strategy for treating this disease.

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 major 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 called HDAC inhibitors 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 it the near future.” He also noted that combining this gene repair strategy with HDAC inhibitors is a possibility.

Kmiec and colleagues are working with the biotechnnology company OrphageniX in Wilmington, Del., on further development of this strategy.