Sunday, 25 March 2012

RNAi: Curing Genetic Disease

RNAi: Curing Genetic Disease

Destined from conception, sufferers of genetic diseases have very poor prospects of finding cures, with most medical treatments only mitigating or slowing symptom progression, condemning them to a curtailed lifespan and reduced quality of life. With the advancement of RNA interference research, a world of possibilities may be uncovered for treatments of genetic disorders that offer effective, long-term solutions.

Autosomal disorders are nearly impossible to cure as the patient’s DNA is the origin of the disease. Both traditional and RNAi treatments attempt to manipulate gene activity or influence gene products such as protein synthesis. However, current pharmacological therapies for genetic disorders have several notable shortcomings, namely the delivery of drugs, targeting and specificity (Seyhan, 2011). Conventional drugs are commonly unable to access and target clinically relevant particles, creating so-called “undruggable” targets. Furthermore, current methodologies lack specificity, frequently unable to act upon target gene sequences without affecting other chemically similar sequences, resulting in undesired, uncontrolled “off-targeting” (Seyhan, 2011). In comparison, RNAi can theoretically be used to silence any gene with pinpoint accuracy, which greatly expands the potential reach of medicine (National Institute of General Medical Sciences, 2012).
Figure 1. Double-stranded RNA (ScienceLibraryPhoto)

Silencing of genes is in essence, sabotaging the process of protein synthesis. Specially modified viral or plasmids vectors are used to introduce double stranded RNA into target cells. Once taken into the host nucleus, the dsRNA undergoes a complex progression of chemical changes. Firstly, RNase III enzymes called Drosha cleave the introduced dsRNA into strands of 60-70 nucleotides known as precursor-microRNA or small hairpin RNA. After being transported from the nucleus to the cytoplasm, another RNase III enzyme called Dicer cleaves the precursor-microRNA to form small interfering RNA, which are 19-25 nucleotides long. The small interfering RNA binds with a protein complex named RISC, and directs the degradation of the complementary mRNA sequence produced by the host cell’s DNA. This is the crucial step which gives RNA interference one of its main advantages over conventional therapies, specificity, as RISC will only activate and destroy mRNA which matches the small interfering RNA bound to it. Degraded mRNA means the defective sequence is not translated and so the mutant protein will not be produced (Seyhan, 2011).

Figure 2. RNA interference process (Seyhan, 2011)

Theoretically, RNAi can alleviate any disorder caused or impacted by proteins, covering a wide range of diseases including HIV, Hepatitus C and Huntington’s Disease. Notably with Huntington’s where defective genes produce toxic proteins especially damaging to motor neurons, there has already been several successful trials on rodents  (National Institute of General Medical Sciences, 2012). By silencing the Huntingtin gene in mice, levels of mutant Htt proteins were reduced with notable improvements in motor function, although challenges remain in improving potency and specificity.
Figure 3. Motor function test on Rotarod (National Phenotyping Center)

Researchers have just started to uncover the potential behind this science and there have been successes with ongoing studies; however, the classic challenges in treating genetic disorders such as drug delivery, targeting and specificity are hampering the development of effective RNAi treatments. Despite this, current scientific understandings show RNAi to be a vast and promising avenue of progress.


National Institute of General Medical Sciences, 2012. RNA Interference Fact Sheet. [Online] Available at: [Accessed 17 March 2012].

National Phenotyping Center, 2008. Rota-rod Test. [Online] Available at: [Accessed 17 March 2012].

ScienceLibraryPhoto, n.d. Double-stranded RNA molecule. [Online] Available at: [Accessed 17 March 2012].

Seyhan, A. A., 2011. RNAi: a potential new class of therapeutic for human genetic disease. Human Genetics, 130(5), pp. 583-605.

Wasi, S., 2003. RNA interference: the next genetics revolution?. [Online] Available at: [Accessed 17 March 2012].


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