Alternative Ways of Splicing RNA
When he first learned about SMA, Dr. Krainer says, "I was extremely excited, because I realized that what we knew about splicing could be applied" to the disease. All the researchers needed to do was to alter the splicing of the second copy of the gene to include the missing piece.
Dr. Krainer and his team sought to change the splicing by introducing synthetic molecules, called antisense oligonucleotides or ASOs, that precisely match various sections of the RNA. They reasoned that if these molecules stuck to the right part of the RNA, they might redirect the splicing process in the desired way. The researchers injected promising ASOs into mice that had an added, human version of the SMN2 gene. As they had hoped, the gene produced much more of the RNA for the critical protein, including the section that is usually omitted, in tissues where the ASOs accumulate.
Before this approach can be tried in patients, several additional issues must be addressed. Researchers will also need to find out, for example, whether the ASOs really benefit growing animals with SMA and how and when they should be administered to affect the nervous system. Still, in contrast to approaches that change splicing patterns for many genes, Krainer expects the highly targeted ASOs may have fewer side effects.
|Contact: Jim Bono|
Cold Spring Harbor Laboratory