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History of RNAi use in medicine

The first instance of RNA silencing in animals was documented in 1996, where Guo and Kemphues observed that, by introducing sense and antisense RNA to par-1 mRNA in Caenorhabditis elegans caused degradation of the par-1 message[1]. It was thought that this degradation was triggered by single stranded RNA (ssRNA), but two years later, in 1998, Fire and Mello. discovered that this ability to silence the par-1 gene expression was actually triggered by double-stranded RNA (dsRNA).[1] They would eventually share the Nobel Prize in Physiology or Medicine for this discovery.[2] Just after Fire and Mello's ground-breaking discovery, Elbashir et al. discovered, by using synthetically made small interfering RNA (siRNA), it was possible to target the silencing of specific sequences in a gene, rather than silencing the entire gene.[3] Only a year later, McCaffrey and colleagues demonstrated that this sequence specific silencing had therapeutic applications by targeting a sequence from the Hepatitis C virus in transgenic mice.[4] Since then, multiple researchers have been attempting to expand the therapeutic applications of RNAi, specifically looking to target genes that cause various types of cancer.[5][6] Finally, in 2004, this new gene silencing technology entered a Phase I clinical trial in humans for wet age-related macular degeneration.[3] Six years later the first-in-human Phase I clinical trial was started, using a nanoparticle delivery system to target solid tumors. [7] Although most research is currently looking into the applications of RNAi in cancer treatment, the list of possible applications is endless. RNAi could potentially be used to treat viruses[8], bacterial diseases[9], parasites[10], maladaptive genetic mutations[11], control drug consumption[12], provide pain relief[13], and even modulate sleep[14].

Therapeutic applications

Viral infection

Antiviral treatment is one of the earliest proposed RNAi-based medical applications, and two different types have been developed. The first type is to target viral RNAs. Many studies have shown that targeting viral RNAs can suppress the replication of numerous viruses, including HIV[15], HPV[16], hepatitis A[17], hepatitis B[18], Influenza virus [19], and Measles virus[20]. The other strategy is to block the initial viral entries by targeting the host cell genes. For example, suppression of chemokine receptors (CXCR4 and CCR5)on host cells can prevent HIV viral entry[21].

Cancer

While traditional chemotherapy can effectively kill cancer cells, lack of specificity for discriminating normal cells and cancer cells in these treatments usually cause severe side effects. Numerous studies have demonstrated that RNAi can provide a more specific approach to inhibit tumor growth by targeting cancer-related genes (i.e., oncogene)[22]. It has also been proposed that RNAi can enhance the sensitivity of cancer cells to chemotherapeutic agents, providing a combinatorial therapeutic approach with chemotherapy.[23] Another potential RNAi-based treatment is to inhibit cell invasion and migration[24].

Neurological diseases

Potential treatments for neurodegenerative diseases have been proposed, with particular attention paid to polyglutamine diseases such as Huntington's disease[25][26].

Previous studies have shown promise in treating human diseases. However, challenges and safety concerns still remain in RNAi-based treatment.  One of the questions revolves around how to deliver RNAi into human cells. A proposed solution to this involved the mode of delivery, and which way the drug can be delivered safely and effectively. Aerosol delivery systems are currently being tested to explore the efficacy of the medication. Scientists developed a variety of delivery strategies, including mechanical and chemical approaches. One of the most promising methods is nanotechnology, which has been widely used in drug delivery.

In this part of Wikipedia assignment, we will update the latest progress in this field and highlight its potential challenges.

Challenges and Applications of siRNA.

Difficulties in Therapeutic Application

To achieve the clinical potential of RNAi, siRNA must be efficiently transportated to the cells of target tissues. However, there are various barriers that must be fixed before it can be used clinically. "Naked" siRNA is susceptible to several obstacles that reduce its therapeutic efficacy.[27] Due to its size and highly polyanionic nature, unmodified siRNA molecules cannot readily enter the cells. Therefore, artificial or nanoparticle encapsulated siRNA must be used. However, transporting siRNA across the cell membrane is still very difficult. Even once the siRNA is transferred, unintended toxicities can occur if therapeutic doses are not optimized, and siRNAs can exhibit off-target effects (e.g. unintended downregulation of genes with partial sequence complementarity).[28] Even after entering the cells, repeated dosing is required since their effects are diluted at each cell division.

File:Naked siRNA Applications.png
A table describing the causes of the challenges of the applications of naked siRNA.

Safety and Uses in Cancer treatment

Compared to chemotherapeutic anti-cancer drugs, there are a lot of advantages of RNAi.[29] RNAi acts on the post-translational step of gene expression, so it does not interact with DNA and thereby avoids the mutation and teratogenicity risks of gene therapy. In a single cancer cell, RNAi can cause dramatic suppression of gene expression with just a few copies. The basic strategy of an RNAi drug is to treat cancer by silencing the specific cancer-promoting gene with rationally designed RNAi. Of course, it is also possible to design effective RNAi drug targeting any disease gene according to the mRNA sequence. Endosomes are then relocated to the lysosomes, which are further acidified and contain various nucleases that promote the degradation of RNAi. The ideal administration route of RNAi is systemic injection so that RNAi can reach cancer cells more efficiently. In addition, the kidney plays a key role in RNAi clearance, such as how siRNA demonstrates the highest uptake in the kidney.

In cancer treatment, RNAi is not as safe as expected. High levels of RNAi result in the activation of the immune response and assists in the production of cytokines in vitro and in vivo. Immune cells express receptors called toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns, including unmethylated CpG DNA and viral dsRNA. Several TLRs are involved in the recognition of siRNA, including TLR3, TLR7, and TLR8. TLR3 is the receptor for dsRNA, and cultured human embryonic kidney HEK-293 cells overexpressing TLR3 are capable of recognizing RNAi. Therefore, chemical modifications and/or delivery methods are required to bring RNAi to its site of action without adverse effects. A broad diversity of materials is under exploration to address the challenges of in vivo delivery, including polymers, lipids, peptides, antibodies, aptamers, and small molecules. Successful systems have been developed by rational design or discovered using high-throughput screening.

http://www.sciencedirect.com/science/article/pii/S1818087614000646

Safety and application of siRNA.

Stimulation of immune response

Some of the RNAi sequences could stimulate innate immune responses. This particularly includes an activation of inflammatory cytokines via nuclear factor κ-light chain enhancer of activated B cells. The innate immune response that bypasses TLR activation is triggered by cytoplasmic RNA sensors, including dsRNA-binding protein kinase.

Another relevant feature of RNAi is its temporary effect. Therefore, in order to study genes with constitutive expression, it is necessary to combine long-term strategies such as the production of transgenic animals encoding short hairpin RNAs(shRNAs) (similar to RNAi) or the use of viral vectors. On the other hand, this temporary characteristic can also be used as an advantage, when one considers RNAi as a therapeutic strategy.

Furthermore, the control of gene expression via RNAi can be modulated in time and directed to specific cells or organs. The identification of viral proteins capable of suppressing RNAi, such as p19 allows for future applications, as well as the use of inducible promoters (high temperature, drugs). All these new developments have led to the first published human clinical trials with very promising results.

Prospects as a Therapeutic Technique

Clinical Phase I and II studies of siRNA therapies conducted between 2015 and 2017 have demonstrated potent (as high as 98%) and durable (lasting for weeks) gene knockdown in the liver, with some signs of clinical improvement and without unacceptable toxicity. Two Phase III studies are in progress to treat familial neurodegenerative and cardiac syndromes caused by mutations in transthyretin (TTR). Numerous publications have shown that in vivo delivery systems are very promising and are diverse in characteristics, allowing numerous applications. The nanoparticle delivery system shows the most promise yet this method presents additional challenges in the scale-up of the manufacturing process, such as the need for tightly controlled mixing processes to achieve consistent quality of the drug product.

  1. ^ a b Sen, George; Blau, Helen (July 2006). "A brief history of RNAi: the silence of the [[gene|genes]]". FASEB. 20: 1293–1299. {{cite journal}}: URL–wikilink conflict (help)
  2. ^ Daneholt, Bertil (October 2, 2006). "The Nobel Prize in Physiology or Medicine 2006". nobelprize.org. Retrieved October 30, 2017. {{cite web}}: Cite has empty unknown parameter: |dead-url= (help)
  3. ^ a b Moffatt, Stanley (December 29, 2016). "siRNA-based Nanoparticles for Cancer Therapy: Hurdles and Hopes" (PDF). MOJ Proteomics & Bioinformatics. 4.
  4. ^ McCaffrey, Anton; Meuse, Leonard; Pham, Thu-Thao; Conklin, Douglas; Hannon, Gregory; Kay, Mark (July 4, 2002). "Gene expression: RNA interference in adult mice". Nature. 418: 38–39.
  5. ^ Devi, GR (September 13, 2006). "siRNA-based approaches in cancer therapy". Cancer Gene Therapy. 9: 819–829 – via PubMed.
  6. ^ Wall, NR; Shi, Y (October 25, 2003). "Small RNA: can RNA interference be exploited for therapy?". Lancet. 362: 1401–1403 – via PubMed.
  7. ^ Davis, ME; Zuckerman, JE; Choi, CH; Seligson, D; Tolcher, A; Alabi, CA; Yen, Y; Heidel, JD; Ribas, A (April 15, 2010). "Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles". Nature. 464: 1067–1070 – via PubMed.
  8. ^ Escobar, MA; Civerolo, EL; Summerfelt, KR; Dandekar, AM (October 30, 2001). "RNAi-mediated oncogene silencing confers resistance to crown gall tumorigenesis". Proceedings of the National Academy of Sciences of the United States of America. 98: 13437–13442 – via PubMed. {{cite journal}}: line feed character in |title= at position 14 (help)
  9. ^ Pereira, T.C.; Pascoal, V.D.B.; Marchesini, R.B.; Maia, I.G.; Magalhães, L.A.; Zanotti-Magalhães, E.M.; Lopes-Cendes, I. (2008/04). "Schistosoma mansoni: Evaluation of an RNAi-based treatment targeting HGPRTase gene". Experimental Parasitology. 118 (4): 619–623. doi:10.1016/j.exppara.2007.11.017. ISSN 0014-4894. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Raoul, Cédric; Abbas-Terki, Toufik; Bensadoun, Jean-Charles; Guillot, Sandrine; Haase, Georg; Szulc, Jolanta; Henderson, Christopher E.; Aebischer, Patrick (April 2005). "Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS". Nature Medicine. 11 (4): 423–428. doi:10.1038/nm1207. ISSN 1078-8956. PMID 15768028.
  11. ^ Ptasznik, Andrzej; Nakata, Yuji; Kalota, Anna; Emerson, Stephen G.; Gewirtz, Alan M. (November 2004). "Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells". Nature Medicine. 10 (11): 1187–1189. doi:10.1038/nm1127. ISSN 1078-8956. PMID 15502840.
  12. ^ Kim, Sung Jin; Lee, Won Il; Lee, Yoon Sun; Kim, Dong Hou; Chang, Jin Woo; Kim, Seong Who; Lee, Heuiran (2009-11-18). "Effective relief of neuropathic pain by adeno-associated virus-mediated expression of a small hairpin RNA against GTP cyclohydrolase 1". Molecular Pain. 5: 67. doi:10.1186/1744-8069-5-67. ISSN 1744-8069. PMC 2785765. PMID 19922668.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  13. ^ Chen, Lichao; McKenna, James T.; Bolortuya, Yunren; Winston, Stuart; Thakkar, Mahesh M.; Basheer, Radhika; Brown, Ritchie E.; McCarley, Robert W. (November 2010). "Knockdown of orexin type 1 receptor in rat locus coeruleus increases REM sleep during the dark period". The European Journal of Neuroscience. 32 (9): 1528–1536. ISSN 1460-9568. PMC 3058252. PMID 21089218.{{cite journal}}: CS1 maint: PMC format (link)
  14. ^ Vargason, Jeffrey M.; Szittya, György; Burgyán, József; Hall, Traci M. Tanka (2003-12-26). "Size selective recognition of siRNA by an RNA silencing suppressor". Cell. 115 (7): 799–811. ISSN 0092-8674. PMID 14697199.
  15. ^ Berkhout, B (2004). "RNA interference as an antiviral approach: targeting HIV-1". Curr Opin Mol Ther. 6(2):141-5.
  16. ^ Jiang, M; Milner, J (2002). "Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference". Oncogene. 21 (39): 6041–8.
  17. ^ Kusov, Y; Kanda, T; Palmenberg, A; Sgro, J; Gauss-Müller, V (2006). "Silencing of Hepatitis A Virus Infection by Small Interfering RNAs". J Virol. 80 (11): 5599–610.
  18. ^ Jia, F; Zhang, Y; Liu, C (2006). "A retrovirus-based system to stably silence hepatitis B virus genes by RNA interference". Biotechnol Lett. 28 (20): 1679–85
  19. ^ Li, Y; Kong, L; Cheng, B; Li, K (2005). "Construction of influenza virus siRNA expression vectors and their inhibitory effects on multiplication of influenza virus". Avian Dis. 49 (4): 562–73.
  20. ^ Hu, L; Wang, Z; Hu, C; Liu, X; Yao, L; Li, W; Qi, Y (2005). "Inhibition of Measles virus multiplication in cell culture by RNA interference". Acta Virol. 49 (4): 227–34
  21. ^ Crowe, S (2003). "Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication, by Martínez et al"
  22. ^ Fuchs, U; Damm-Welk, C; Borkhardt, A. "Silencing of disease-related genes by small interfering RNAs". Curr Mol Med. 4(5):507-17.
  23. ^ Cioca, D.P.; Aoki, Y; and Kiyosawa, K (2003). "RNA interference is a functional pathway with therapeutic potential in human myeloid leukemia cell lines". Cancer Gene Therapy. 10, 125–133 doi:10.1038/sj.cgt.7700544
  24. ^ Lapteva, N; Yang, AG; Sanders, DE; Strube, RW; Chen, SY (2005). "CXCR4 knockdown by small interfering RNA abrogates breast tumor growth in vivo". Cancer Gene Ther. 12(1):84-9.
  25. ^ Raoul, C; Barker, S; Aebischer, P (2006). "Viral-based modeling and correction of neurodegenerative diseases by RNA interference". Gene Ther. 13 (6): 487–95. PMID 16319945. doi:10.1038/sj.gt.3302690.
  26. ^ Harper, SQ; Staber, PD; He, X; Eliason, SL; Martins, IH; Mao, Q; Yang, L; Kotin, RM; Paulson, HL and Davidson, BL (2005). "RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model". PNAS. 102 (16): 5820–5825, doi: 10.1073/pnas.0501507102
  27. ^ Kanasty, Rosemary; Dorkin, Joseph Robert; Vegas, Arturo; Anderson, Daniel (2013-10-23). "Delivery materials for siRNA therapeutics". Nature Materials. 12 (11): nmat3765. doi:10.1038/nmat3765.
  28. ^ Wittrup, Anders; Lieberman, Judy (2015-9). "Knocking down disease: a progress report on siRNA therapeutics". Nature reviews. Genetics. 16 (9): 543–552. doi:10.1038/nrg3978. ISSN 1471-0056. PMC 4756474. PMID 26281785. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  29. ^ Xu, Cong-fei; Wang, Jun (2015-02-01). "Delivery systems for siRNA drug development in cancer therapy". Asian Journal of Pharmaceutical Sciences. 10 (1): 1–12. doi:10.1016/j.ajps.2014.08.011.
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