Shooting the Messenger (RNA) in the Neurology Clinic: The Promise of Therapeutic RNA Interference

By Pedro Gonzalez-Alegre, MD

January 2, 2008


Science Editorials and Reviews ā€“ Edited by David Riley, MD

This editorial was developed for, which is publishing expert opinions on a variety of hot topics in neurology.

Pedro Gonzalez-Alegre, MD
Department of Neurology
Carver College of Medicine at The University of Iowa
Author Disclosure


The discovery of RNA interference (RNAi) is one of the more important scientific breakthroughs in the last ten years. RNAi is currently being evaluated in the laboratory and in human therapeutic trials for its ability to silence the expression of disease-related genes. There are several questions about therapeutic RNAi that are of interest to the practicing neurologist.

The discovery of RNA interference (RNAi) is among the more important scientific breakthroughs of past decade, a fact which was underscored by the Nobel Prize awarded to Fire and Mello for their extraordinary discovery.1 RNAi technology has undergone rapid development and is found in research settings ranging from biochemistry laboratories to human therapeutics trials. The therapeutic potential is receiving much attention in clinical neuroscience.

What is RNAi?

RNAi regulates post-transcriptional gene expression by way of short double-stranded RNAs which recognize and trigger the destruction of specific messenger RNAs (mRNA), thus precluding translation into a protein (Figure). RNAi have been manipulated in many ways, from the functional characterization of individual genes to novel therapeutic applications as gene therapy.

Figure 1 - By triggering the degradation of specific messenger RNAs (mRNA), small interfering RNAs (siRNA) prevent their translation into disease-linked proteins, thus preventing the downstream pathogenic cascade.

What are the principles of therapeutic RNAi?

The therapeutic use of RNAi can be viewed as the opposite of more traditional modalities of gene therapy. Historically, gene therapy protocols aimed to replace defective genes in affected neurons, or to express proteins such as growth factors that would create a favorable environment for diseased neurons. Therefore, diseases caused by loss of protein function represent ideal candidates for traditional gene therapy. The goal of RNAi, on the other hand, is to "silence" the expression of genes whose expression leads to detrimental effects. These therapeutic molecules function by "shooting the messenger (RNA)" in host cells.
  • Because the exquisite specificity of these RNA duplexes allows them to discriminate between sequences differing by a single nucleotide, virtually any mRNA can be targeted.
  • Dominantly inherited diseases where the gene mutations result in novel toxic properties of the protein product represent the most commonly explored targets in experimental RNAi neurotherapeutics.
  • In sporadic diseases, key genes in the pathogenic cascade can be silenced with the aim of halting the pathogenic process, regardless of whether a mutant gene or wild type gene is involved.

Where do we stand on therapeutic RNAi development for neurological diseases?

Studies in cultured cells established the feasibility of using RNAi to silence disease-linked genes, and once efficient delivery of RNAi-mediating vectors into mammalian neurons in vivo was achieved, the road towards the design of therapeutic trials in animal models was paved. The first successful report of this intervention in a transgenic mouse model of spinocerebellar ataxia type 1 (SCA1) came in 2004,2 and subsequently reports followed in animal models of Huntington's disease, familial ALS, Alzheimer's disease and prion disease (reviewed in 3). As one example, BACE1, an enzyme involved in APP processing and required for AƟ deposition, is currently being explored as an RNAi target in sporadic and inherited Alzheimer's disease.

What are the hurdles? Where to go now?

The success of preclinical trials in rodents placed us on the path towards the use of RNAi in the neurology clinic. This journey, however, is being hindered by the obstacles of delivery and safety.

  • Delivery has been the biggest hurdle to overcome in the advance of nucleic acid-based therapies for brain disorders. However, research in this field is rapidly advancing with two parallel fronts: viral and non-viral delivery technologies. Encouraging progress in both modalities, such as the development of safer and more efficient neurotropic viruses and modified synthetic siRNAs, make the development of optimized, safe and effective delivery methods just a matter of time.
  • A second issue that needs to be solved is whether the exogenous manipulation of this pathway could cause deleterious consequences. In a recent study, mice that received large amounts of short hairpin RNA (shRNA) targeting genes in the liver, suffered massive hepatocyte death. The authors showed that the highly expressed shRNAs interfered with normal function of the endogenous RNAi pathway (microRNA). In the nervous system, the microRNA pathway plays a major role in processes such as neuronal development and differentiation, and has itself been implicated in the pathogenesis of developmental disorders. Therefore, interruption of normal microRNA function must be avoided. Strategies to minimize these potential ill effects will be necessary.

In conclusion, we can be cautiously optimistic about the use of therapeutic RNAi for neurological disorders. This therapeutic modality has been already used in human trials for macular degeneration, and reports in other non-neurological diseases will soon appear. Trials for diseases such as SCA1, familial ALS or Huntington's disease could be a reality earlier than expected.


  1. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998;391(6669):806-811.
  2. Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT, et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 2004;10(8):816-820.
  3. Gonzalez-Alegre P, Paulson HL. Technology insight: therapeutic RNA interference--how far from the neurology clinic? Nat Clin Pract Neurol 2007;3(7):394-404.


Dr. Gonzalez-Alegre has received research grant funding from NIH/NINDS, Dystonia Medical Research Foundation, Bachmann-Strauss Dystonia & Parkinson Foundation and the Children's Miracle Network.