Silencing Toxic Genes

MMD, FSHD, OPMD, and some forms of EDMD and ALS, might benefit from new strategy

by Quest Staff on April 18, 2009 - 9:00pm

A new gene therapy approach to "silencing" disease-causing genetic information has been developed by researchers at Rutgers University in Piscataway, N.J., and Integrated DNA Technologies in Coralville, Ia.

The approach could have application in such muscle diseases as myotonic dystrophy (MMD), facioscapulohumeral dystrophy (FSHD), one form of Emery-Dreifuss MD (EDMD), oculopharyngeal MD (OPMD) and the SOD1-related form of amyotrophic lateral sclerosis (ALS).

Although most people think of “gene therapy” as adding therapeutic genes to compensate for genes that are nonfunctional, this approach isn't helpful in genetic diseases where errors in DNA cause the production of dangerous proteins, a process scientists call a toxic gain of function.

Gene therapy for diseases caused by toxic gains of function involves blocking or silencing genes, rather than inserting new genes.

Samuel Gunderson and Rafal Gorcazniak at Rutgers and Mark Behlke at Integrated DNA Technologies, who published their findings online Feb. 25, 2009, in Nature Biotechnology, say they've developed a new gene silencing strategy that may have advantages over existing approaches.

cell diagram
Cells affected by type 1 myotonic dystrophy have a toxic gain of function in the RNA made from the DMPK gene. The RNA acts in a toxic way, trapping a protein called muscleblind and causing cellular dysfunction. U1 adaptors have the potential to destroy this type of toxic RNA.

Destroying toxic RNA

Their strategy involves using compounds called "U1 adaptors." U1 adaptors are synthetic nucleic acid molecules that stick to the targeted genetic information (the RNA, which is made from a gene's DNA) on one end and to a protein called U1snRNP on the other. This indirect tethering of the U1snRNP protein to the target RNA causes the cell to destroy the RNA.

Normally, the U1snRNP protein participates in a process called splicing, during which some parts of the RNA are removed (spliced out) and a final RNA is constructed. The final RNA becomes the genetic recipe the cell follows to make protein molecules.

Errors in the final RNA can be toxic themselves or lead to harmful errors in the final protein. In addition, errors that cause too much of the final protein to be produced also contribute to -- and in some cases cause -- disease. Silencing problematic RNA molecules would have therapeutic value, Gunderson says.

The investigators reduced levels of two human proteins -- one involved in cholesterol distribution and the other a cancer-causing gene -- using the U1 adaptor gene silencing strategy.

Advantages over other strategies

The investigators say the experimental strategies currently being used to silence genes (known as antisense and RNA interference) are limited by their need to interact with specific cellular enzymes. They believe the U1 adaptors might be useful for a wider range of situations because they lack this requirement.

They also note that the U1 adaptors have limited unwanted effects, do not appear to affect normal splicing of RNA, and don't contain structures known to trigger an unwanted immune response.

"Although their practical use remains speculative," the authors write, "several considerations support the prospect of using U1 adaptors ... for therapeutic indications."

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