Editing Small interfering RNA (section)

== Therapies ==
A decade after the discovery of [[RNA interference|RNAi]] mechanism in 1993, the pharmaceutical sector heavily invested in the research and development of siRNA therapy. There are several advantages that this therapy has over small molecules and antibodies. It can be administered quarterly or every six months. Another advantage is that, unlike small molecule and monoclonal antibodies that need to recognize specific conformation of a protein, siRNA functions by [[Watson-Crick helix|Watson-Crick]] basepairing with mRNA. Therefore, any target molecule that needs to be treated with high affinity and specificity can be selected if the right nucleotide sequence is available.<ref name = "Hu_2020" /> One of the biggest challenges researchers needed to overcome was the identification and establishment of a delivery system through which the therapies would enter the body. And that the immune system often mistakes the RNAi therapies as remnants of infectious agents, which can trigger an immune response.<ref name = "Eisenstein_2019" /> Animal models did not accurately represent the degree of immune response that was seen in humans and despite the promise in the treatment investors divested away from RNAi.<ref name = "Eisenstein_2019" />

However, there were a few companies that continued with the development of RNAi therapy for humans. [[Alnylam Pharmaceuticals]], [[Sirna Therapeutics]] and Dicerna Pharmaceuticals are few of the companies still working on bringing RNAi therapies to market. It was learned that almost all siRNA therapies administered in the bloodstream accumulated in the liver. That is why most of the early drug targets were diseases that affected the liver. Repeated developmental work also shed light on improving the chemical composition of the [[RNA]] molecule to reduce the immune response, subsequently causing little to no side effects.<ref>{{cite journal | vauthors = Tiemann K, Rossi JJ | title = RNAi-based therapeutics-current status, challenges and prospects | journal = EMBO Molecular Medicine | volume = 1 | issue = 3 | pages = 142–51 | date = June 2009 | pmid = 20049714 | pmc = 3378126 | doi = 10.1002/emmm.200900023 }}</ref> Listed below are some of approved therapies or therapies in pipeline.

=== Alnylam Pharmaceuticals ===
In 2018, [[Alnylam Pharmaceuticals]] became the first company to have a siRNA therapy approved by the [[Food and Drug Administration|FDA]]. [[Patisiran|Onpattro (patisiran)]] was approved for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) [[amyloidosis]] in adults. hATTR is a rare, progressively debilitating condition. During hATTR amyloidosis, misfolded transthyretin (TTR) protein is deposited in the extracellular space. Under typical folding conditions, TTR tetramers are made up of four monomers. Hereditary ATTR amyloidosis is caused by a fault or mutation in the transthyretin (TTR) gene which is inherited. Changing just one amino-acid changes the tetrameric transthyretin proteins, resulting in unstable tetrameric transthyretin protein that aggregates in monomers and forms insoluble extracellular amyloid deposits. Amyloid buildup in various organ systems causes cardiomyopathy, polyneuropathy, gastrointestinal dysfunction. It affects 50,000 people worldwide. To deliver the drug directly to the liver, siRNA is encased in a lipid nanoparticle. The siRNA molecule halts the production of amyloid proteins by interfering with the RNA production of abnormal TTR proteins. This prevents the accumulation of these proteins in different organs of the body and helps the patients manage this disease.<ref>{{Cite journal|last1=Yonezawa|first1=Sei|last2=Koide|first2=Hiroyuki|last3=Asai|first3=Tomohiro|date=2020|title=Recent advances in siRNA delivery mediated by lipid-based nanoparticles|journal=Advanced Drug Delivery Reviews|volume=154|pages=64–78|doi=10.1016/j.addr.2020.07.022|issn=0169-409X|pmc=7406478|pmid=32768564}}</ref><ref>{{Cite web|last=Commissioner|first=Office of the|date=2020-03-24|title=FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease|url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-targeted-rna-based-therapy-treat-rare-disease|archive-url=https://web.archive.org/web/20190531082749/https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-targeted-rna-based-therapy-treat-rare-disease|url-status=dead|archive-date=31 May 2019|access-date=2021-05-24|website=FDA|language=en}}</ref>

Traditionally, liver transplantation has been the standard treatment for hereditary transthyretin amyloidosis, however its effectiveness may be limited by the persistent deposition of wild-type transthyretin amyloid after transplantation. There are also small molecule medications that provide temporary relief. Before Onpattro was released, the treatment options for hATTR were limited. After the approval of Onpattro, FDA awarded Alnylam with the Breakthrough Therapy Designation, which is given to drugs that are intended to treat a serious condition and are a substantial improvement over any available therapy. It was also awarded Orphan Drug Designations given to those treatments that are intended to safely treat conditions affecting less than 200,000 people.<ref>{{cite press release |title=FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease |publisher=U.S. Food and Drug Administration |date=10 August 2018 |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-targeted-rna-based-therapy-treat-rare-disease |archive-url=https://web.archive.org/web/20190531082749/https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-targeted-rna-based-therapy-treat-rare-disease |url-status=dead |archive-date=31 May 2019 }}</ref>

Along with Onpattro, another RNA interference therapeutic drug has also been discovered (Partisiran) which has property of inhibiting hepatic synthesis of transthyretin. Target messenger RNA (mRNA) is cleaved as a result by tiny interfering RNAs coupled to the [[RNA-induced silencing complex]]. Patisiran, an investigational RNAi therapeutic drug, uses this process to decrease the production of mutant and wild-type transthyretin by cleaving on 3-untranslated region of transthyretin mRNA.<ref>{{cite journal |last1=David |first1=Adams |title=Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis |journal=The New England Journal of Medicine |date=July 5, 2018 |volume=379 |issue=1 |pages=11–21 |doi=10.1056/NEJMoa1716153 |pmid=29972753 |doi-access=free |hdl=2445/138257 |hdl-access=free }}</ref>

In 2019, FDA approved the second RNAi therapy, [[Givosiran|Givlaari (givosiran)]] used to treat acute hepatic porphyria (AHP). The disease is caused due to the accumulation of toxic [[porphobilinogen]] (PBG) molecules which are formed during the production of heme. These molecules accumulate in different organs and this can lead to the symptoms or attacks of AHP.

Givlaari is an siRNA drug that downregulates the expression of [[Aminolevulinic acid synthase|aminolevulinic acid synthase 1]] (ALAS1), a liver enzyme involved in an early step in heme production. The downregulation of ALAS1 lowers the levels of neurotoxic intermediates that cause AHP symptoms.<ref name = "Hu_2020" />

Years of research has led to a greater understanding of siRNA therapies beyond those affecting the liver. As of 2019, Alnylam Pharmaceuticals was involved in therapies that may treat [[amyloidosis]] and CNS disorders like [[Huntington's disease]] and [[Alzheimer's disease]].<ref name = "Eisenstein_2019" /> They have also partnered with [[Regeneron Pharmaceuticals]] to develop therapies for CNS, eye and liver diseases.

As of 2020, ONPATTRO and GIVLAARI, were available for commercial application, and two siRNAs, [[lumasiran]] (ALN-GO1) and [[inclisiran]], have been submitted for new drug application to the FDA. Several siRNAs are undergoing phase 3 clinical studies, and more candidates are in the early developmental stage.<ref name = "Hu_2020" /> In 2020, Alnylam and Vir pharmaceuticals announced a partnership and have started working on a RNAi therapy that would treat severe cases of COVID-19.<ref>{{Cite web|title=Vir and Alnylam Expand Collaboration to Advance Investigational RNAi Therapeutics Targeting Host Factors for t|url=https://investors.alnylam.com/press-release?id=24696|access-date=2021-05-24|website=Investor Relations {{!}} Alnylam Pharmaceuticals, Inc.|language=en}}</ref>

Other companies that have had success in developing a pipeline of siRNA therapies are Dicerna Pharmaceuticals, partnered [[Eli Lilly and Company]] and [[Arrowhead Pharmaceuticals]] partnered with [[Johnson & Johnson|Johnson and Johnson]]. Several other big pharmaceutical companies such as [[Amgen]] and [[AstraZeneca]] have also invested heavily in siRNA therapies as they see the potential success of this area of biological drugs.<ref>{{Cite web|title=Alnylam and Dicerna are pals now, which could spell trouble for Arrowhead|url=https://www.biopharmadive.com/news/alnylam-dicerna-collaboration-antitrypsin-rna-arrowhead/575543/|access-date=2021-05-24|website=BioPharma Dive|language=en-US}}</ref>