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For instance, siRNAs were able to bind specifically to tumor suppressor p53 molecules containing a single point mutation and destroy it, while leaving the wild-type suppressor intact. Receptors involved in mitogenic pathways that lead to the increased production of cancer cells there have also been targeted by siRNA molecules. The chemokine receptor chemokine receptor 4 CXCR4 , associated with the proliferation of breast cancer, was cleaved by siRNA molecules that reduced the number of divisions commonly observed by the cancer cells.
Antiapoptotic proteins, such as clusterin and survivin , are often expressed in cancer cells. For instance, mice implanted with colon adenocarcinoma cells were found to survive longer when the cells were pretreated with siRNAs that targeted B-catenin in the cancer cells. Viral genes and host genes that are required for viruses to replicate or enter the cell, or that play an important role in the life cycle of the virus are often targeted by antiviral therapies.
RNAi has been used to target genes in several viral diseases, such as the human immunodeficiency virus HIV and hepatitis.
In hepatitis B, siRNA silencing was used to target the surface antigen on the hepatitis B virus and led to a decrease in the number of viral components. RNA interference has been in commercial use to control virus diseases of plants for over 20 years see Plant disease resistance. In —, multiple examples of "coat protein-mediated resistance" against plant viruses were published, before RNAi had been discovered. Potato lines expressing viral replicase sequences that confer resistance to potato leafroll virus were sold under the trade names NewLeaf Y and NewLeaf Plus, and were widely accepted in commercial production in —, until McDonald's Corp.
Gene silencing techniques have also been used to target other viruses, such as the human papilloma virus , the West Nile virus , and the Tulane virus. The E6 gene in tumor samples retrieved from patients with the human papilloma virus was targeted and found to cause apoptosis in the infected cells. Unlike viruses, bacteria are not as susceptible to silencing by siRNA.
Bacteria replicate outside of the host cell and do not contain the necessary machinery for RNAi to function. Ribozymes, antisense oligonucleotides, and more recently RNAi have been used to target mRNA molecules involved in asthma. Huntington's disease HD results from a mutation in the huntingtin gene that causes an excess of CAG repeats.
Gene silencing can be used to treat HD by targeting the mutant huntingtin protein.
The mutant huntingtin protein has been targeted through gene silencing that is allele specific using allele specific oligonucleotides. In this method, the antisense oligonucleotides are used to target single nucleotide polymorphism SNPs , which are single nucleotide changes in the DNA sequence, since HD patients have been found to share common SNPs that are associated with the mutated huntingtin allele. Non-allele specific gene silencing using siRNA molecules has also been used to silence the mutant huntingtin proteins. Through this approach, instead of targeting SNPs on the mutated protein, all of the normal and mutated huntingtin proteins are targeted.
At this level, they found that the mice developed improved motor control and a longer survival rate when compared to the controls.
Amyotrophic lateral sclerosis ALS , also called Lou Gehrig's disease , is a motor neuron disease that affects the brain and spinal cord. The disease causes motor neurons to degenerate, which eventually leads to their death. There are several challenges associated with gene silencing therapies, including delivery and specificity. For instance, in the case of neurodegenerative disorders, gene silencing molecules must be delivered to the brain. The blood-brain barrier makes it difficult to deliver molecules into the brain by preventing the passage of the majority of molecules that are injected or absorbed into the blood.
Once inside the brain, however, the molecules must move inside of the targeted cells. In order to efficiently deliver siRNA molecules into the cells, viral vectors can be used. In addition to delivery, specificity has also been found to be an issue in gene silencing. Arctic Apples are a suite of trademarked [70] apples that contain a nonbrowning trait create by using gene silencing to reduce the expression of polyphenol oxidase PPO It is the first approved food product to use that technique.
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