• • Antisense oligonucleotides • • • mRNAs summarized in inthefieldwithinpastfew years,substantial dealactivity as based drugsseemsto beonthehorizon, andthere hasbeen crop anew oftherapies. ofnucleic-acid- Nevertheless, delivery and majorchallengesremain, suchastheefficientandtargeted trials— asmallnumberoftherapies are inlate-stage new—only many of the othermarket, platforms in the field are still relatively (see below). microRNA-based agentsandmessengerRNA(mRNA)-based RNAs (siRNAs),acid-based drugsincludingsmallinterfering otides, companies are of nucleic- now other types also exploring such asoncologyandmetabolism. rare geneticdisorders, aswell asfor more commondiseasesinareas nologies to modulate gene expression and create therapies for new have beenpursuingthedevelopment ofnucleic-acid-basedtech For more decades, than two and biotech pharmaceutical companies BioPharma Dealmakers or to promote oftherapeutic theproduction proteins has spurred astring of recent deals. proteinsThe of disease-associated drugs potentialto halttheproduction of nucleic-acid-based drugs nucleic-acid-based Unravelling of potential the • • • • • Administration (FDA) in1998 to treat retinitis cytomegalovirus Vitravene () wasapproved by theUS Food andDrug proteins havedisease-associated reached themarket: Two antisenseoligonucleotides thatinhibittheexpression of encoded protein. degradation andthereby inhibitingtheproductionof oligonucleotide thenbindsto themRNA,leadingto its protein. disease-associated particular The antisense to thesequenceofmRNAthatencodesa complementary Synthetic antisenseoligonucleotidescanbedesigned to be replacement therapies, are stages ofdevelopment. atearly clinically tested. Arangeofotherapplications, includingprotein and mRNAvaccinesfor infectious diseaseshave alsobeen mRNAs have reached ascancer immunotherapies, phase3trials encoded antigens. animmuneresponse asvaccinesthattrigger to the function can beusedto generate therapeuticproteins ofinterest or Through called translation. encoded ingenesto guide thesynthesisofproteins inaprocess mRNAs are alarge familyofRNAs thatconvey information Although afew antisenseoligonucleotides have madeitto the approachesBuilding onpioneering usingantisenseoligonucle ex vivo Figure 1 transfection orvaccination,syntheticmRNAs . - - • • • MicroRNAs • • • siRNAs • • • • • • • • 2013. Boththerapieswere developed by Ionis the FDA familialhypercholesterolemia for homozygous in discontinued) andKynamro ()wasapproved by in immunocompromised patients(althoughitisnow disease areas. being investigated inoncology andother asbiomarkers therapeutics have reached phase2trials. MicroRNAs are also including cancerandviralinfections, andafew of these and microRNA mimics, are beingexplored to target diseases therapeutics,MicroRNA-based includingmicroRNA inhibitors multiple genes. mRNAs, andsoasinglemicroRNA canregulate theexpression of microRNAs to theirtarget are notcompletely complementary into proteins. However, whereas siRNAs target aspecificgene, Similar to siRNAs, microRNAs inhibitthetranslationof mRNAs the regulation ofgeneexpression through RNAi. RNAsMicroRNAs thathave are smallnon-coding acentralrole in been approved. therapies have reached clinicaldevelopment, butnonehasyet monogenic disorders cancers. andvarious siRNA-based Multiple geneisdesirable, suchasrare which silencingofaparticular siRNAs are alsobeinginvestigated astherapeuticsfor diseasesin identification ofpotential drugtargets. employed includingthe instudiesofgenefunction, specific genesofinterest, andsiRNA technologies are widely vectors, theRNAiprocess canbeusedto harness to silence Chemically synthesized siRNAs, orexpression ofsiRNAs from viral protein expression. mRNAs, thusreducingthe degradation ofcomplementary assiRNAs andleadsto RNAs known of smalldouble-stranded regulates geneexpression. The process involves theproduction RNA-mediated interference(RNAi)isanaturalprocess that agents are inclinicaldevelopment. with Duchennemusculardystrophy, andotherexon-skipping approval by theFDA for thetreatment ofasubsetpatients ), hasrecently beengranted accelerated agent,ExondysOne exon-skipping 51(eteplirsen; developed by involved ingenesplicing, thereby leadingto ‘exon skipping’. accessofproteinsto target RNAsequencesandblocking by binding Another classofantisenseoligonucleotidefunctions (aSanoficompany), respectively. andGenzyme ) withCIBA Pharmaceuticals, inpartnerships Vision (aunitof biopharmadealmakers.nature.com |November 2016 |

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feature feature B8 agents. Figure recent 1:Selected deals since 2014involving nucleic-acid-based Value –undisclosed –February 2016 Date treatments for Alzheimerdisease develop microRNA-based Universit research agreement with BiosignsMicrolin alicenseand Value –undisclosed –February 2015 Date an siRNA-basedcancerdrug to develop with NanoCarrier technology, Chugaipartners nucleic-acid-delivery Using NanoCarrier’s NanoFect $115 millioninmilestone payments Value –$175millionupfront andupto 2014 –January Date Merck Sirna from Therapeutics subsidiary acquires |November 2016 | investment Value –$700millionstock 2014 –January Date and America Western Europe Pharmaceuticals outsideofNorth product pipelineofAlnylam toto therare licenserights diseases Sanofi’s unitgainsoptions Genzyme Deals are colour-coded according areDeals to colour-coded theplatform involved. é Laval to jointly biopharmadealmakers.nature.com $617 millioninmilestone payments Value –$57millionupfront andupto –September 2016 Date therapies for cardiovascular diseases tion dealsto develop RNAi-based cals sign licensingandcollabora- two andArrowhead Pharmaceuti- $1,560 millioninmilestone payments Value –$10millionupfront andupto 2015 –October Date diseases mRNA-based therapeuticsfor rare Arcturus Therapeutics to develop collaboration andlicensingdealwith Pharmaceutical signs a

Value –$35million –March 2015 Date Research Corporation and assetsto Arrowhead sellsitsRNAibusiness Novartis 2016 undisclosed milestone payments Value –$125millionupfront and 2014 –January Date diseases mRNA-based therapeuticsfor rare Therapeutics to develop collaborates withModerna milestone payments and upto $1.9billionin Value –$710millionupfront 2014 –April Date disease antisense drugfor Crohn Pharma’s oral late-stage Celgene acquires Nogra milestone payments and upto $871millionin Value –$40millionupfront 2016 –May Date metabolic diseases acid-based therapeuticsfor to develop nucleic- partner Wave Life andPfizer Sciences Value –undisclosed –February 2014 Date therapeutics for four targets to develop microRNA-based withSanofi-Aventis partnership Regulus Therapeutics renews its million inmilestone androyalty payments Value –$40millionupfront andupto $275 –July2016 Date fibrosistherapeutics for cystic Therapeutics to develop mRNA-based withModerna partners mRNA, mRNA, and near-term milestone payments Value –upto $310millioninupfront –September 2016 Date cancer vaccines BioNTech AG to develop mRNA-based collaborates with RNA; TGFβ2, transforming growth β2. factor messenger ~$4 billioninmilestone payments Value –$65millionupfront andupto –August 2015 Date and renal diseases drugs for cardiovascular, metabolic Pharmaceuticals to develop antisense withIonis AstraZeneca partners Value –undisclosed 2014 –January Date technology platform Horizon Discovery’s siRNA cancer drugtargets screened from exclusive licenseto validated AstraZeneca isgranted an Value –undisclosed 2015 –October Date Therapeutics Isarna from oligonucleotide trabedersen TGF Autotelic to the buystherights β2-specific antisense 2015 RNA; RNAi, RNA-mediated interference; siRNA, small interfering RNA; RNAi,RNA-mediated interference; siRNA,smallinterfering Value –undisclosed –June2016 Date (pembrolizumab)inhibitor Keytruda withMerck’sin trials checkpoint mRNA-based vaccinesandtest these with Merck to develop personalized Therapeutics signs adeal $205 millioninpotential milestone payments Value –Undisclosedupfront payment and –July2014 Date undisclosed target develop anmRNA-basedvaccineagainst CureVac andSanofiPasteur collaborate to programs in milestone payments thatcovers three Value –$10millionandupto $800million –July2016 Date 2015) disorders (original dealinJanuary antisense drugindicated for gastrointestinal agreement withJanssenBiotech for anoral Ionis Pharmaceuticals signs alicensing payments to $100millioninmilestone Value –$2.5millionupfront andup –NovemberDate 2015 antisense platform for renal diseases undisclosed moleculesfrom Idera’s Idera Pharmaceuticals to develop collaboratesGlaxoSmithKline with Value –undisclosed 2014 –April Date diseases anddystrophies treatment ofneuromuscular microRNA-based productsfor the Biotech to developMarina with partners Genomics Rosetta undisclosed milestones Value –$2millionupfront plus –August 2014 Date multiple sclerosis discover in microRNA biomarkers dealwithBiogenIdectonew Regulus Therapeutics signs a milestone payments and upto $200millionin Value –$250millionupfront –August 2014 Date Pharma and mRNAspecialistSantaris acquiresRoche themicroRNA

microRNA-based agents siRNA-based agents Antisense oligonucleotides mRNA-based agents 2014