HD Lighthouse Contributing Editor's Comment: Scientists have been making revolutionary strides by controlling the expression of genes, changing the way that cells “read” DNA and translate it into use. One new tool is the gene-silencing technique known as RNA interference (RNAi). RNAi continues to show great therapeutic potential after just a decade of experimental use. It can be used to precisely turn off (or lower) the amount of a specific protein that is produced by any particular gene. This ability is obviously of great interest for Huntington’s disease, which is characterized by the production of a mutant, toxic protein, as well as for similar neurological diseases.

In fact, RNAi has been used to lower the level of mutant huntingtin protein in brain with remarkable success in animal models. Beyond that, RNAi has reversed Huntington’s motor deficits in mouse models, even after the disease has significantly advanced in the mice [1-3].

But several large questions must be answered before RNAi can be turned to therapeutic use in people.

First, consider how RNAi therapy now works in animal models.

Normally, when a gene is “read” by a cell, the gene (DNA) is transcribed into messenger RNA (mRNA). Then the mRNA travels outside the cell nucleus to be translated into a functioning protein. (Normal and mutant huntingtin are examples of proteins produced like this, like many thousands of other proteins in our bodies.)

In RNAi therapy, experimenters introduce small pieces of RNA that are exactly complementary to sections of this messenger RNA, injecting the RNA pieces into individual cells in vitro or an animal’s brain in vivo. The small, introduced pieces of RNA glom onto to the complementary mRNA in various ways, preventing that mRNA from being translated into the protein in question. As a result, in the case of Huntington’s, less mutant huntingtin protein is produced, and the nerve cells normally affected by mutant huntingtin suffer less harm, while the mouse itself (and hopefully the person with Huntington’s) suffers less cognitive and motor damage. For more information on how RNAi works, the Alnylam Phamaceuticals website offers various educational materials, including NOVA materials and video segment (link to page at alnylam.com; link to page at pbs.org ).

RNAi has some very notable advantages as a therapeutic approach, beyond its gene-targeting precision:

• First, it addresses the disease process at an “upstream” point, soon after the undesirable gene (such as the mutant huntingtin gene) has been transcribed into mRNA and before it has been translated into the mutant (huntingtin) protein. This special kind of intervention also means that genes can in effect be turned off (or down) without making any changes in a person’s genome (genetic material).
• Second, it turns out that RNAi can partly silence a gene, which may itself be a valuable characteristic. In some cases, a smaller amount of a protein still needs to be produced, because it must function at some level to sustain the cell. This is true of the huntingtin protein, among others.
• Third, RNAi can target events in the disease process that would otherwise be impossible to reach using small molecules and other standard pharmaceutical approaches. RNAi can reach so-called “non-druggable targets.”
• Finally, RNAi has now been used successfully to target just a single allele of a gene, the mutant allele, and silence that allele but not the remaining allele of the pair. That is, the normal (or wild-type) allele remains in business, producing the nonmutant protein that cells need. Such allele-specific targeting represents a special opportunity in addressing dominant disease genes (such as Huntington’s). The mutant allele can be turned off, while the wild-type allele can continue to produce the normal protein that the cell requires.

It is the delivery method for RNAi that presents the greatest challenges in bringing RNAi to human clinical use. There is some concern that introduced RNAi may not act selectively enough in the brain, for example. It may also be necessary to provide ongoing delivery of RNAi to be sure therapeutic effects are seen over the longer run. These and some other important aspects of RNAi delivery must be ironed out before the technique is ready for testing in people.

Nevertheless, as the Lighthouse has reported (see links below), there have already been stunning successes using gene silencing in animals. A recent review article by Dr. Dinah Sah of Alnylam Pharmaceuticals (see abstract below) reports on the growing promise of RNAi techniques, in terms of their variety and their applicability to a range of neurological diseases. Among other developments, RNAi has now been delivered directly (without the help of virus vectors) and successfully in HD and other disease models.

• For more information on RNAi research in mouse models of HD and other neurological diseases, see --
  http://www.hdlighthouse.org/research/genetherapy/updates/0057RNAi.php
  http://www.www.hdlighthouse.org/research/genetherapy/updates/1147rnai.php
  http://www.hdlighthouse.org/research/drugs-supps/updates/1142rnai.php
• For more general information on RNAi, see --
  http://www.hdlighthouse.org/see/research/geneoff.htm
  , as well as the Alnylam material mentioned earlier —
  http://www.alnylam.com/science-technology/index.asp
  http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html

Text references

1. Díaz-Hernàndez, Miguel, et al. 2005. Full motor recovery despite striatal neuron loss and formation of irreversible amyloid-like inclusions in a conditional mouse model of Huntington’s disease. J Neurosci, Oct. 19, 25(42):9773-9781.
   (http://www.jneurosci.org/cgi/content/full/25/42/9773)
   
2. Harper, Scott Q., et al. 2005. RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Nat Acad of Sci, Apr. 19, 102(16):5820-5825.
   (http://www.pnas.org/cgi/content/full/102/16/5820)
   
3. Sah, Dinah. See abstract below. (link to page at ncbi.nlm.nih.gov)

-- Ann Covalt, M.A.
Posted to the HDL: 06 Aug 2006

Therapeutic potential of RNA interference for neurological disorders

Dinah W.Y. Sah

During the past decade, numerous molecular mediators of neurodegenerative diseases and neurological disorders have been identified and validated, yet few novel therapies have emerged and the unmet medical needs remain high. These molecular mediators belong to target classes such as ion channels, neurotransmitters and neurotransmitter receptors, cytokines, growth factors, enzymes and other proteins. In some cases, substantial pre-clinical validation exists, but the molecular target has not been readily druggable with small molecules, proteins or antibodies. RNA interference represents a therapeutic approach applicable to such non-druggable targets. Both non-viral and viral delivery strategies are being undertaken for in vivo silencing of molecular targets by RNA interference, which has resulted in robust efficacy in animal models of Alzheimer's disease, ALS, Huntington's disease, spinocerebellar ataxia, anxiety, depression, neuropathic pain, encephalitis and glioblastoma. These proof-of-concept data in animal models, together with the commencement of clinical trials using RNA interference for macular degeneration and respiratory syncytial virus infection, point to the potential of direct RNA interference for neurological disorders and neurodegenerative diseases. # # #

Source: LIfe Sciences 2006 Jun 15; [Epub ahead of print]

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