Two separate teams of researchers from the UK and Switzerland used a gene therapy approach to interfere with the faulty SOD1 gene in mice. Interfering with faulty genes may slow down the progression of motor neurone disease.
Tests suggest that the technique of RNA interference, while not a cure, can slow this fatal nerve wasting illness.
About 10% of cases are inherited, caused by at least 100 different mutations in a protein known as SOD1. Mice, genetically engineered to carry this faulty human gene, developed a disease that looks like human ALS. Each team was able to show that they could delay the disease's effects and help their genetically engineered mice live longer. Different lentiviruses, long-lived viruses related to HIV that are good at delivering genetic material to cells were used by the two the teams. The researchers disabled the viruses, then they genetically engineered them to carry a specific sequence of the genetic material RNA. This interferes with the faulty RNA that the mutant human SOD1 genes in the mice produce.
By using lentiviruses to silence the mutant genes considerable therapeutic benefit was provided by delaying onset and prolonging the duration of motor neurone disease, said Professor Patrick Aebischer of the Swiss Federal Institute of Technology in Lausanne, Switzerland.
The UK team injected its gene therapy into the spines and various muscles of the ALS mutant mice and when Dr Mimoun Azzouz of Oxford Biomedica and colleagues dissected the mice, they found the treated mice had more healthy motor neurones than untreated mice.
It took twice as long as normal for ALS symptoms to start and the mice lived for 80% of their normal lifespan.
Upon close examination of several SAT pairs, Abe's group found that the transcripts shared several striking characteristics. Northern blot hybridization analyses of six randomly chosen SAT pairs revealed that the SAT loci generated multiple transcripts of various sizes, in contrast to a single transcript that is expected under the traditional one gene-one transcript model. Furthermore, the SATs tended to be poly(A)-negative and enriched in the nucleus, which strongly suggests a functional role for these transcripts in gene regulation.
Abe and Kiyosawa also evaluated four Arabidopsis SAT pairs and demonstrated that these molecular characteristics were largely conserved in plants.
"Conventional belief in molecular biology suggests that poly(A)+ mRNAs are major mediators in flows of genetic information," Abe explains. "However, the information obtained from this study implies that some classes of poly(A)-negative nuclear RNA may have important biological functions."
Among these functions may be the regulation of gene expression on a domain level, such as that which has been documented for several imprinted loci. Antisense transcripts have been shown to alter the methylation status of the overlapping partner gene. SATs might also trigger posttranscriptional gene regulation via RNA interference (RNAi) by virtue of their ability to form double-stranded RNA (dsRNA) molecules.
A large proportion of these antisense RNAs represent non-coding RNAs. Thus, the researchers expect that these results will lead to a better understanding of roles of non-coding RNAs in gene regulation.
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