Scientists at three U.S. institutions have used a very small synthetic molecule to correct the genetic defect in cells taken from a person with spinal muscular atrophy (SMA), a disease in which muscle-controlling nerve cells in the spinal cord are lost.
The multicenter research team, which published results in the July-August-September 2009 issue of RNA Biology, was coordinated by MDA grantee Ravindra Singh at Iowa State University in Ames. The team also included MDA-supported Laxman Gangwani at the Medical College of Georgia in Augusta.
The molecule the researchers developed is called an "antisense oligonucleotide," a type of compound that's being used experimentally in a number of genetic diseases to block the effects of abnormal genetic material (see MMD Research: "Bright" Prospect) or to cause cells to skip over erroneous genetic instructions (see Success of 'Exon-Skipping' Strategy).
In SMA, the compound is being used to mask genetic instructions that, when present, result in the synthesis of a short, nonfunctional protein.
Antisense oligonucleotides have been used this way previously in SMA, but the molecules have been larger. The new, smaller version has potential advantages for both safety and effectiveness, the researchers say.
SMA is a disease that involves profound weakness or paralysis of voluntary muscles. In its most severe form, known as type 1 SMA, it affects infants, causing impairment of the breathing and swallowing muscles. Type 1 SMA is usually fatal within the first few years of life. Types 2, 3 and 4 SMA affect children and adults, causing varying degrees of loss of strength and mobility.
The molecular cause of the disease is a deficiency of a protein called SMN, which stands for "survival of motor neurons." The gene from which this protein is made is located on chromosome 5 and is known as SMN1.
The SMN1 gene is missing in people with SMA. However, one or more copies of a second gene, called SMN2, are located on chromosome 5 in people with (and without) SMA, and a small amount of functional SMN protein can be made from this gene. The more copies of SMN2 a person has, the better he or she is able to compensate for the loss of the SMN1 gene.
|Genetic information moves from its storage form as DNA to a set of instructions known as RNA, from which protein molecules are made. Most of the RNA instructions from the SMN1 gene tell the cell to make full-length SMN protein. Most of the instructions from the SMN2 gene tell the cell to make short SMN protein. Antisense to mask some of the instructions in the SMN2 RNA can cause synthesis of full-length SMN from the SMN2 gene.|
About SMA Therapies
One promising line of research in SMA is coaxing more SMN protein synthesis from the SMN2 genes a person has. (See Spinal Muscular Atrophy In Focus.)
The "rough draft" genetic instructions (technically known as "pre-RNA") made from the SMN2 gene contain a code that allows nerve cells to omit a section known as "exon 7" from the final genetic instructions (known as "messenger RNA").
Antisense and other molecular strategies are designed to override this instruction, encouraging cells to include exon 7 in the final RNA instructions.
Evidence from laboratory experiments strongly suggests that adequate levels of exon-7-containing RNA would result in synthesis of adequate amounts of full-length, fully functional SMN protein and would arrest the loss of motor neurons in SMA.
If you or a family member has any type of SMA, you're invited to join the International SMA Patient Registry. The Registry is a database that can be used, with participants' permission, by clinicians and scientists as an informational resource and recruitment tool for clinical trials. Joining the Registry in no way commits you to participation in any research project but does allow you to be notified about such projects.
The Registry is supported by the Patient Advisory Group of the International Coordinating Committee for SMA Clinical Trials, which includes MDA, Families of SMA, Fight SMA, the SMA Foundation and other SMA advocacy groups. It's housed at Indiana University School of Medicine.