HD Lighthouse Contributing Editor's Comment: This is an exciting development in RNAi research. For RNAi therapy to work, we need a safe, efficient delivery system (called a vector) to get the short interfering pieces of RNA into the vulnerable brain cells to disrupt the production of mutant HD. Viral vectors are efficient but may have some safety risks. The advantage of a nonviral vector is that there are no protein factors to cause an adverse response. The advantage to using the Sleeping Beauty transposon system is that it appears to provide continuous suppression of the mutated gene.

This new nonviral gene therapy involves a transposon. Transponsons are DNA segments which migrate into chromosomes and carry genetic information. This particular transponson was 'reawakened' from a fossil fish gene, dormant for 15 million years. Since it's discovery by University of Minneosota researcher Perry Hackett of the University of Minnesota in 1997, researchers have been busy investigating its potential in gene therapy.

The University of Minnesota researchers formed a company to further gene therapy using the Sleeping Beauty transposon system, Discovery Genomics. http://www.discoverygenomics.net/ This company is hoping to begin clinical trials for Franconi anemia and is doing preclinical work on hemophilia A.

The current study shows that this technology coupled with short interfering RNA can suppress 90 percent of the mutated HD protein in a cell model for five months. The researchers plan to continue their work with HD mice and are in the process of deciding which transgenic model to use. This is research to watch!

Read more about the Sleeping Beauty Transposon System, click here: http://www.seagrant.umn.edu/seiche/2002/06/no_rest_for_sleeping_beauty.html
--Marsha L. Miller, Ph.D.
Posted to the HDL: 03 Mar 2005

Sleeping Beauty-mediated down-regulation of huntingtin expression by RNA interference.

Huntington disease (HD) is a devastating neurologic disorder that is characterized by abnormal expansion of a CAG nt repeat in the first exon of the huntingtin (htt) gene, producing a mutant protein with an elongated polyglutamine stretch. The presence of this mutant protein is correlated with the characteristic loss of striatal neurons and the clinical manifestation of HD. Currently there is no effective treatment for the associated cell death. The aim of this study was to evaluate an innovative strategy combining RNA interference (RNAi) and gene transfer via the nonviral Sleeping Beauty (SB) transposon system to down-regulate Htt expression. siRNA expression vectors were designed to target exons 1, 4, 6, and 62 of the human htt gene. Real-time RT-PCR and Western blot analysis were used to quantify Htt mRNA and protein levels, respectively, in human cell lines. The results indicated that selected siRNA constructs significantly decreased Htt mRNA and protein levels relative to controls. In addition, SB transposition of the siRNA constructs into the genome reduced long-term protein expression of Htt by approximately 90%. The combination of siRNA, the SB transposon, and an accurate transgenic mouse model may permit evaluation of this approach in preventing the pathogenesis associated with expression of mutant Htt.

Tracked on the Lighthouse:
RNAi

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Source: Biochem Biophys Res Commun. 2005 Apr 8;329(2):646-52.

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