Zorro-LNA: A New Way to Turn off Genes

HD Lighthouse Contributing Editor's Comment: Researchers have developed a new way to turn off genes. The method that we are familiar with is RNA interference which blocks the message to make the protein. The method described below involves a locked nucleic acid (LNA) which binds to both strands of the double-helix structure of DNA and blocks the actual instructions on how to make the protein.

This is of interest to the HD community since it may turn out to be more effective than RNAi. However, the same problem exists - how can the abnormal gene be turned off without turning off the normal one since they are so similar? Further, there is one big additional problem - delivery. RNAi can be delivered by viral vectors but LNAs cannot.

At this point, RNAi continues to look more promising. It's efficiency has been improving and it may be already efficient enough for treatment purposes. Still, it is good to have a backup technique in development.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 18 May 2007

Locked Neucleic Acids (LNAs) are synthetic analogs of nucleic acids that contain a bridging methlyene carbon between the 2' and 4' positions of the ribose ring. In this study, we generated a novel, sequence-specific antigene molecule "Zorro-LNA", which simultaneously binds to both strands, and that induced effective and specific strand invasion into DNA duplexes and potent inhibition of gene transcription, also in a cellular context. By comparing the Zorro LNA with linear LNA as well as an optimized bisPNA (peptide nucleic acid) oligonucleotide directed against the same target sites, respectively, we found that the Zorro LNA construct was unique in its ability to arrest gene transcription in mammalian cells. To our knowledge, this is the first time in mammalian cells that gene transcription was blocked by a nucleic acid analog in a sequence-specific way using low but saturated binding of a blocking agent. This offers a novel type of antigene drug that is easy to synthesize.

The Press Release

Scientists find new agent to fight genetic disorders -- Zorro-Locked Nucleic Acid

A study to appear in the June 2007 issue of The FASEB Journal describes a new agent, called "Zorro-LNA," which has the potential to stop genetic disorders in their tracks. In the study, researchers from the Karolinska Institute in Stockholm, Sweden, describe how they developed Zorro-LNA to bind with both strands of a gene’s DNA simultaneously, effectively disabling that gene. This development has clinical implications for virtually every human condition caused by or worsened by dominant defective genes. Examples include: Huntington’s disease, familial high cholesterol, polycystic kidney disease, some instances of glaucoma and colorectal cancer, and neurofibromatosis, among others.

"Zorro-LNA is a new substance that targets DNA and turns off genes," said co-author Edvard Smith of the Karolinska Institute in Sweden. "It has the potential of becoming a new drug for the treatment of human genetic disease."

The findings described in this article significantly raise the possibility that new therapies could arise where defective DNA is deactivated more completely and more thoroughly than ever before. For instance, Zorro-LNA could be used in combination with "RNA interference" (RNAi). Like Zorro-LNA, RNAi has the ability to deactivate genes, but does so by degrading the gene’s RNA. In addition, Zorro-LNA could be used to deactivate certain genes in stem cells, which could eventually lead to the development of new cells, tissues, or organs. The discovery of RNAi was recognized by a Nobel Prize award in 2006 to two American scientists.

"This is a major development in the treatment not only of genetic diseases, but also of acquired diseases when microbes or toxins cause genes to go awry" said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "One might say these researchers have found a gene-hunter’s Holy Grail for which scientists have been hunting for many years. Zorro-LNA should give us a new, safe way of blocking the effects of errors in our genetic repertoire."

Source: The Federation of the American Societies for Experimental Biology Vol. 21 (June 2007):1-13.

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