History of RNAi use in medicine
![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/59/Vertical_Timeline_of_RNAi%27s_Use_in_Medicine.pdf/page1-270px-Vertical_Timeline_of_RNAi%27s_Use_in_Medicine.pdf.jpg)
The first instance of RNA silencing in animals was documented in 1996, when 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 extensive. 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
editViral infection
editAntiviral 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
editWhile 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
editRNAi strategies also show potential for treating neurodegenerative diseases. Studies in cells and in mouse have shown that specifically targeting Amyloid beta-producing genes (e.g. BACE1 and APP) by RNAi can significantly reduced the amount of Aβ peptide which is correlated with the cause of Alzheimer's disease.[25][26][27] In addition, this silencing-based approaches also provide promising results in treatment of Parkinson's disease and Polyglutamine disease.[28][29][30]
Difficulties in Therapeutic Application
editTo 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. For example, "Naked" siRNA is susceptible to several obstacles that reduce its therapeutic efficacy.[31] Additionally, once siRNA has entered the bloodstream, naked RNA can be degraded by serum nucleases and can stimulate the innate immune system.[32] Due to its size and highly polyanionic (containing negative charges at several sites) nature, unmodified siRNA molecules cannot readily enter the cells through the cell membrane. Therefore, artificial or nanoparticle encapsulated siRNA must be used. However, transporting siRNA across the cell membrane still has its own unique challenges. If siRNA is transferred across the cell membrane, 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).[33] Even after entering the cells, repeated dosing is required since their effects are diluted at each cell division.
Safety and Uses in Cancer treatment
editCompared with chemotherapy or other anti-cancer drugs, there are a lot of advantages of siRNA drug.[34] SiRNA acts on the post-translational stage of gene expression, so it doesn’t modify or change DNA in a deleterious effect.[34] SiRNA can also be used to produced a specific response in a certain type of way, such as by downgrading suppression of gene expression.[34] In a single cancer cell, siRNA can cause dramatic suppression of gene expression with just several copies.[34] This happens by silencing cancer-promoting genes with RNAi, as well as targeting an mRNA sequence.[34]
RNAi drugs treat cancer by silencing certain cancer promoting genes.[34] This is done by complementing the cancer genes with the RNAi, such as keeping the mRNA sequences in accordance with the RNAi drug.[34] Ideally, RNAi is should be injected and/or chemically modified so the RNAi can reach cancer cells more efficiently.[34] RNAi uptake and regulation is monitored by the kidneys.[34]
Stimulation of immune response
editThe human immune system is divided into two separate branches: the innate immune system and the adaptive immune system.[35] The innate immune system is the first defense against infection and responds to pathogens in a generic fashion.[35] On the other hand, the adaptive immune system, a system that was evolved later than the innate, is composed mainly of highly specialized B and T cells that are trained to react to specific portions of pathogenic molecules.[35]
The challenge between old pathogens and new has helped create a system of guarded cells and particles that are called safe framework.[35] This framework has given humans an army systems that search out and destroy invader particles, such as pathogens, microscopic organisms, parasites, and infections.[35] The mammalian safe framework has developed to incorporate siRNA as a tool to indicate viral contamination, which has allowed siRNA is create an intense innate immune response.[35]
siRNA is controlled by the innate immune system, which can be divided into the acute inflammatory responses and antiviral responses.[35] The inflammatory response is created with signals from small signaling molecules, or cytokines.[35] These include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12) and tumor necrosis factor α (TNF-α).[35] The innate immune system generates inflammation and antiviral responses, which cause the release pattern recognition receptors (PRRs).[35] These receptors help in labeling which pathogens are viruses, fungi, or bacteria.[35] Moreover, the importance of siRNA and the innate immune system is to include more PRRs to help recognize different RNA structures.[35] This makes it more likely for the siRNA to cause an immunostimulant response in the event of the pathogen.[35]
Prospects as a Therapeutic Technique
editClinical Phase I and II studies of siRNA therapies conducted between 2015 and 2017 have demonstrated potent and durable gene knockdown in the liver, with some signs of clinical improvement and without unacceptable toxicity.[36] Two Phase III studies are in progress to treat familial neurodegenerative and cardiac syndromes caused by mutations in transthyretin (TTR).[37] 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.[38] The table below shows different drugs using RNA interference and what their phases and status is in clinical trials.[31]
Drug | Target | Delivery System | Disease | Phase | Status | Company | Identifier |
ALN–VSP02 | KSP and VEGF | LNP | Solid tumours | I | Completed | Alnylam Pharmaceuticals | NCT01158079 |
siRNA–EphA2–DOPC | EphA2 | LNP | Advanced cancers | I | Recruiting | MD Anderson Cancer Center | NCT01591356 |
Atu027 | PKN3 | LNP | Solid tumours | I | Completed | Silence Therapeutics | NCT00938574 |
TKM–080301 | PLK1 | LNP | Cancer | I | Recruiting | Tekmira Pharmaceutical | NCT01262235 |
TKM–100201 | VP24, VP35, Zaire Ebola L-polymerase | LNP | Ebola-virus infection | I | Recruiting | Tekmira Pharmaceutical | NCT01518881 |
ALN–RSV01 | RSV nucleocapsid | Naked siRNA | Respiratory syncytial virus infections | II | Completed | Alnylam Pharmaceuticals | NCT00658086 |
PRO-040201 | ApoB | LNP | Hypercholesterolaemia | I | Terminated | Tekmira Pharmaceutical | NCT00927459 |
ALN–PCS02 | PCSK9 | LNP | Hypercholesterolaemia | I | Completed | Alnylam Pharmaceuticals | NCT01437059 |
ALN–TTR02 | TTR | LNP | Transthyretin-mediated amyloidosis | II | Recruiting | Alnylam Pharmaceuticals | NCT01617967 |
CALAA-01 | RRM2 | Cyclodextrin NP | Solid tumours | I | Active | Calando Pharmaceuticals | NCT00689065 |
TD101 | K6a (N171K mutation) | Naked siRNA | Pachyonychia congenita | I | Completed | Pachyonychia Congenita Project | NCT00716014 |
AGN211745 | VEGFR1 | Naked siRNA | Age-related macular degeneration, choroidal neovascularization | II | Terminated | Allergan | NCT00395057 |
QPI-1007 | CASP2 | Naked siRNA | Optic atrophy, non-arteritic anterior ischaemic optic neuropathy | I | Completed | Quark Pharmaceuticals | NCT01064505 |
I5NP | p53 | Naked siRNA | Kidney injury, acute renal failure | I | Completed | Quark Pharmaceuticals | NCT00554359 |
Delayed graft function, complications of kidney transplant | I, II | Recruiting | Quark Pharmaceuticals | NCT00802347 | |||
PF-655 (PF-04523655) | RTP801 (Proprietary target) | Naked siRNA | Choroidal neovascularization, diabetic retinopathy, diabetic macular oedema | II | Active | Quark Pharmaceuticals | NCT01445899 |
siG12D LODER | KRAS | LODER polymer | Pancreatic cancer | II | Recruiting | Silenseed | NCT01676259 |
Bevasiranib | VEGF | Naked siRNA | Diabetic macular oedema, macular degeneration | II | Completed | Opko Health | NCT00306904 |
SYL1001 | TRPV1 | Naked siRNA | Ocular pain, dry-eye syndrome | I, II | Recruiting | Sylentis | NCT01776658 |
SYL040012 | ADRB2 | Naked siRNA | Ocular hypertension, open-angle glaucoma | II | Recruiting | Sylentis | NCT01739244 |
CEQ508 | CTNNB1 | Escherichia coli-carrying shRNA | Familial adenomatous polyposis | I, II | Recruiting | Marina Biotech | Unknown |
RXi-109 | CTGF | Self-delivering RNAi compound | Cicatrix scar prevention | I | Recruiting | RXi Pharmaceuticals | NCT01780077 |
ALN–TTRsc | TTR | siRNA–GalNAc conjugate | Transthyretin-mediated amyloidosis | I | Recruiting | Alnylam Pharmaceuticals | NCT01814839 |
ARC-520 | Conserved regions of HBV | DPC | HBV | I | Recruiting | Arrowhead Research | NCT01872065 |
![]() | This is a user sandbox of Horrockssam. You can use it for testing or practicing edits. This is not the sandbox where you should draft your assigned article for a dashboard.wikiedu.org course. To find the right sandbox for your assignment, visit your Dashboard course page and follow the Sandbox Draft link for your assigned article in the My Articles section. |
References
edit- ^ a b Sen, George; Blau, Helen (July 2006). "A brief history of RNAi: the silence of the [[gene]]s". FASEB. 20 (9): 1293–1299. doi:10.1096/fj.06-6014rev. PMID 16816104. S2CID 12917676.
{{cite journal}}
: URL–wikilink conflict (help)CS1 maint: unflagged free DOI (link) - ^ Daneholt, Bertil (October 2, 2006). "The Nobel Prize in Physiology or Medicine 2006". nobelprize.org. Retrieved October 30, 2017.
- ^ a b Moffatt, Stanley (December 29, 2016). "siRNA-based Nanoparticles for Cancer Therapy: Hurdles and Hopes" (PDF). MOJ Proteomics & Bioinformatics. 4 (6). doi:10.15406/mojpb.2016.04.00142. S2CID 23010713.
- ^ 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 (6893): 38–39. doi:10.1038/418038a. PMID 12097900. S2CID 4361399.
- ^ Devi, GR (September 13, 2006). "siRNA-based approaches in cancer therapy". Cancer Gene Therapy. 13 (9): 819–829. doi:10.1038/sj.cgt.7700931. PMID 16424918. S2CID 23475841 – via PubMed.
- ^ Wall, NR; Shi, Y (October 25, 2003). "Small RNA: can RNA interference be exploited for therapy?". Lancet. 362 (9393): 1401–1403. doi:10.1016/S0140-6736(03)14637-5. PMID 14585643. S2CID 25034627 – via PubMed.
- ^ 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 (7291): 1067–1070. doi:10.1038/nature08956. PMC 2855406. PMID 20305636 – via PubMed.
- ^ 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 (23): 13437–13442. doi:10.1073/pnas.241276898. PMC 60889. PMID 11687652 – via PubMed.
- ^ 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. PMID 18237732.
{{cite journal}}
: Check date values in:|date=
(help) - ^ 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. S2CID 25445264.
- ^ 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. S2CID 21770360.
- ^ 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: unflagged free DOI (link) - ^ 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. doi:10.1111/j.1460-9568.2010.07401.x. ISSN 1460-9568. PMC 3058252. PMID 21089218.
- ^ 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. doi:10.1016/s0092-8674(03)00984-x. ISSN 0092-8674. PMID 14697199. S2CID 12993441.
- ^ Berkhout, B (2004). "RNA interference as an antiviral approach: targeting HIV-1". Curr Opin Mol Ther. 6(2):141-5.
- ^ 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.
- ^ 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.
- ^ 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
- ^ 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.
- ^ 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
- ^ Crowe, S (2003). "Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication, by Martínez et al"
- ^ Fuchs, U; Damm-Welk, C; Borkhardt, A. "Silencing of disease-related genes by small interfering RNAs". Curr Mol Med. 4(5):507-17.
- ^ 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
- ^ 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.
- ^ Singer, O; Marr, RA; Rockenstein, E; Crews, L; Coufal, NG; Gage, FH; Verma, IM; Masliah, E (2005). "Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model". Nat Neurosci. 8(10):1343-9.
- ^ Rodríguez-Lebrón, E; Gouvion, CM; Moore, SA; Davidson, BL; Paulson HL (2009). "Allele-specific RNAi mitigates phenotypic progression in a transgenic model of Alzheimer's disease". Mol Ther. 17(9):1563-73.
- ^ Piedrahita, D; Hernández, I; López-Tobón, A; Fedorov, D; Obara, B; Manjunath, BS; Boudreau, RL; Davidson, B; Laferla, F; Gallego-Gómez, JC; Kosik, KS; Cardona-Gómez, GP (2010). "Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer's mice". J Neurosci. 30(42):13966-76.
- ^ 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.
- ^ 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
- ^ Boudreau, RL; Rodríguez-Lebrón E; Davidson, BL (2011). "RNAi medicine for the brain: progresses and challenges". 20(R1): R21–R27.
- ^ a b Kanasty, Rosemary; Dorkin, Joseph Robert; Vegas, Arturo; Anderson, Daniel (2013-10-23). "Delivery materials for siRNA therapeutics". Nature Materials. 12 (11): 967–977. doi:10.1038/nmat3765. PMID 24150415.
- ^ Kanasty, Rosemary; Dorkin, Joseph Robert; Vegas, Arturo; Anderson, Daniel (2013-10-23). "Delivery materials for siRNA therapeutics". Nature Materials. 12 (11): 967–977. doi:10.1038/nmat3765. ISSN 1476-4660. PMID 24150415.
- ^ 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) - ^ a b c d e f g h i 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.
- ^ a b c d e f g h i j k l m Whitehead, Kathryn A.; Dahlman, James E.; Langer, Robert S.; Anderson, Daniel G. (2011). "Silencing or stimulation? siRNA delivery and the immune system". Annual Review of Chemical and Biomolecular Engineering. 2: 77–96. doi:10.1146/annurev-chembioeng-061010-114133. ISSN 1947-5438. PMID 22432611.
- ^ Wittrup, Anders; Lieberman, Judy (2015-08-18). "Knocking down disease: a progress report on siRNA therapeutics". Nature Reviews Genetics. 16 (9): 543–552. doi:10.1038/nrg3978. PMC 4756474. PMID 26281785.
- ^ Wittrup, Anders; Lieberman, Judy (2015). "Knocking down disease: a progress report on siRNA therapeutics". Nature Reviews Genetics. 16 (9): 543–552. doi:10.1038/nrg3978. PMC 4756474. PMID 26281785.
- ^ Kanasty, Rosemary; Dorkin, Joseph Robert; Vegas, Arturo; Anderson, Daniel (2013-10-23). "Delivery materials for siRNA therapeutics". Nature Materials. 12 (11): 967–977. doi:10.1038/nmat3765. ISSN 1476-4660. PMID 24150415.