Therapeutics

Current t rends in RNA- based t hera peutic devel op ment

Cellular play crucial roles during disease progression and represent a diverse and largely untapped class of biomolecules that can be exploited for drug development.

By Dr Xiaoqiu Wu NA species include messenger RNAs l Antisense RNAs, or RNA interference (RNAi) and Dr Andrew P. (mRNAs) that are translated into proteins, via miRNAs and siRNAs, to partially or complete - Turnbull Rlong non-coding RNAs including transfer ly turn off expression. RNAs (tRNAs) and ribosomal RNAs (rRNAs), and l RNA , or ‘chemical ’, which small non-coding RNAs such as micro RNAs bind to specific molecular targets and can act as (miRNAs) and small interfering RNAs (siRNAs). drug carriers to deliver small-molecule chemother - Exploiting RNA species as therapeutic agents offers apeutics, siRNAs, miRNAs or nanoparticles into new opportunities for drug developers, and the pos - targeted tissues. sibility to develop agents against ‘undruggable’ and gene products (for a comprehensive review on These efforts have led to the therapeutic poten - RNA-targeted therapeutics, please refer to reference tial of RNA drugs being realised 2, with the RNA 1). Furthermore, new screening tools now make it – (brand name Macugen) – easier to target disease-associated RNA sequences. representing the first FDA approval for an RNA- However, developing RNA-based therapeutics is not based drug in 2004. Since then, two antisense without its challenges since RNA is inherently unsta - RNAs – nusinersen (Spinraza) and eteplirsen ble and prone to degradation by active and abundant (Exondys 51) – and one siRNA drug – patisiran ribonucleases (RNases), is potentially immunogenic (Onpattro) – have gained FDA approval ( Table and may require a delivery vehicle for efficient and 1). As of July 2018, 69 companies have mRNA, specific transport to target cells and across the lipid antisense RNA, RNAi or RNA aptamer therapeu - bilayer. These development hurdles have largely been tics in clinical development with 315 ongoing overcome by chemically modifying RNA to enhance clinical trials (data provided by GlobalData Plc; its stability, and by employing synthetic carriers such https://www.globaldata.com/ ). Furthermore, sev - as lipid nanoparticle (LNP) or polymer-based eral strategic collaborations and partnerships nanoparticle (PNP) systems for RNA drug delivery. have been forged between big Pharma and RNA drug development efforts have primarily Biotech companies to leverage proprietary tech - focused on four modalities: nology platforms. For example, Arbutus Biopharma Corporation, which has proprietary l mRNA vaccines for and infectious disease. LNP and ligand-conjugate delivery technologies, l In vitro transcribed (IVT) mRNAs to replace or recently entered into an agreement with Roivant supplement proteins. Sciences to launch Genevant Sciences. New

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Table 1: RNA-based therapeutics in clinical development. RNA drugs in five or more clinical trials as of July 2018 are tabulated. Data provided by GlobalData Plc

Cl ass Co mpany Dr ug Th erapeutic In dication Cl inical De velopment (Bra nd Nam e) Area Tri als Sta ge (! 5)

mR NA Ar gos Ro capuldencel-T On cology Mu scle Invasive Bladder Cancer (MI BC); Non- 9 Ph ase II Th erapeutics Inc Sm all Cell Lu ng Cancer; AGS -004 In fe ctious Hu ma n Immu nodeficiency Vi rus (HI V) 6 Ph ase II Dis ease In fe ctions (A ID S) eT heR NA Tr iMix-ba sed On cology Me lanoma; Mu ltiple My eloma (Kahler Disease) 6 Ph ase II Im munothera pies im munoth erapy NV Bo ehringer BI -1361849 On cology No n-Sm all Cell Lu ng Cancer 5 Ph ase II In gelheim GmbH

An tisense Bi ogen Inc Nu sinersen Ce ntral Ner vous Sp inal Muscular Atrophy (SM A) 13 Ma rketed RNA (S pinra za) Sys tem Ak cea Vo lanesorsen Me tabolic Fa milial Ch ylomicronemia (Type I 13 Pr e-re gistra tion Th erapeutics Inc so dium Dis orders Hy perlipoproteinemi a) Sa repta Et eplirsen Ge netic Du chenne Muscular Dy strophy 12 Ma rketed Th erapeutics Inc (E xondys 51) Dis orders An tisense AT L1102 Ce ntral Ner vous Re lapsing Re mitting Mu ltiple Sclerosis (RRMS ); 8 Ph ase II Th erapeutics Lt d Sys tem Se condary Pr ogressive Multiple Sc lerosis (S PMS) Ph armaxis Lt d AS M-8 Re spiratory Al lergic As thma 6 Ph ase II

si RNA Th e Medicines In clisira n Ca rdiovascular At herosclerosis; Ca rdiovascular Disease 11 Ph ase III Co mpany Met ab olic Ho mo zygous Fami lial Dis orders Al nylam Pa tisiran Me tabolic He reditary transthyretin-me diated amy loidosis 8 Ma rketed Ph armaceuticals (O npattro ) Dis orders (h ATTR) In c RX i RX I-109 De rma tology Hy pertrophic Scars 8 Ph ase II Ph armaceuticals Co rp Opht ha lmol ogy We t (Neovascular/Exudative) Ma cular De generation Al nylam Fi tusiran Haem at ological He mo philia A; He mo philia B 7 Ph ase III Ph armaceuticals Dis orders In c Ce mdisiran Ga strointestina At ypical He mo lytic Ur emi c Syndrome 7 Ph ase II (N ondiarrh ea- As sociated He mo lytic Ur emi c Sy ndrome) Haem at ological Pa roxysmal Nocturnal Haem oglobinuria Dis orders Qu ark QP I-1002 Ge nito Uri nary Ac ute Renal Failure (AR F) (Ac ute Ki dney 6 Ph ase III Ph armaceuticals Sys tem And In jury ) In c Sex Hor mone s

Immu nology Ki dney Transplant Rejection Br istol-My ers BM S-986263 Ga strointestinal Li ver Fi brosis 6 Ph ase II Sq uibb Co Pf izer Inc PF -655 Me tabolic Di abetic Macular Edema 5 Ph ase II Dis orders

Opht ha lmol ogy We t (Neovascular/Exudative) Ma cular De generation

RNA Pf izer/Valeant Pe gaptanib Op hthalmo logy Ag e-Rel at ed Macu lar Deg en er at ion (A MD) 38 Ma rketed Ph armaceuticals (M acugen) Apt amer In tern ational In c Op hthotech Corp Av acincaptad Op hthalmo logy Dr y (Atr ophic ) Macu lar Deg en er at ion 11 Ph ase III pe gol sodi um (Z imura ) No xxon Pharma Ol aptesed pegol On cology B-Cel l Chr oni c Lym phoc yt ic Leu kem ia 11 Ph ase II AG Em apticap pegol On cology So ld Tum our 5 Ph ase II

Met ab olic Dia betic Nep hropat hy Dis orders

modalities to target RNA are also being devel - Development hurdles oped including the application of CRISPR-Cas9 Despite the potential of RNA therapeutics, efficient editing technology and the development ! and safe delivery remains a significant challenge. ! of selective small-molecule modulators of RNA or There are a number of significant issues that need to RNA-modifying enzymes. The global RNA drugs be overcome in their development: instability and market is forecast to exceed $10 billion by 2024 immunogenicity; rapid clearance from the blood by (based on an analysis carried out using the the kidneys and liver scavenger receptors; cellular GlobalData Plc database), highlighting the signif - uptake and endosomal escape 3. These hurdles can icant commercial potential of this emerging class be overcome by chemically modifying RNA and by of therapeutics. using improved synthetic delivery carriers 4.

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Chemical modification are to use endosomolytic agents such as fusogenic mRNAs can be stabilised by incorporating natural - peptides and polymers to enhance endosomal ly-occurring modified nucleosides including pseu - escape of siRNAs 7. douridine, which represents one of the most abun - dant post-transcriptional RNA modifications, and Classes of RNA-based therapeutics the more recently identified 5’-methyl-cytidine RNA-based therapies can be classified according to triphosphate (m 5CTP), N 6-methyl-adenosine-5’- their mechanism of action and include single- triphosphate (m 6ATP), 2-thio-uridine triphosphate stranded mRNAs and antisense RNAs, double- (s2UTP), N 6-methyladenosine (m 6A), and N 6,2-O- stranded miRNAs and siRNAs, and RNA 6 5,6 dimethyladenosine (m Am) . In addition, a 5’cap, aptamers ( Figure 1 ). RNA-based therapeutics optimised 3’ poly(A) tail, and 5’- or 3’- untranslated range in size from thousands of bases for mRNAs regions can be added or the mRNA can be codon down to 8-50 nucleotides for antisense RNAs and optimised to improve translational efficiency. 20-25 base pairs for miRNAs and siRNAs. Modified mRNAs can reduce immunogenicity and increase protein expression levels compared with mRNA unmodified mRNA. The most common chemical IVT mRNA is single-stranded and comprises struc - modifications that have been incorporated to tural features in common with native mRNA, with enhance the stability of RNAi and antisense RNA its bioavailability being determined by RNase drugs are phosphorothioate RNA backbone modi - degradation, delivery and cytosolic translocation. fications and ribose modifications including 2’-O- IVT mRNAs usually incorporate chemically modi - methyl, 2’-fluoro and 2’-O-methylethyl substitu - fied nucleosides such as pseudouridine, which tions 7. These modifications enhance the stability of reduce immunogenicity and increase its transla - the RNA drug and provide protection from nucle - tional efficiency 9. Furthermore, the development ase degradation. Furthermore, the new chemistries of improved formulations, for example the use of confer drug-like properties to RNA, reduce immune LNPs and PNPs, protect IVT mRNAs from stimulation, maximise on-target potency and pro - RNases and facilitate cellular uptake ( Figure 1 ). long the duration of the drug. IVT mRNA can potentially be used to transient - ly express proteins to prevent or alter a disease Delivery state, with mRNA drugs being developed for can - RNA-based therapeutics must be delivered to the cer immunotherapies and infectious disease, pro - target cell and enter the cell to be active 8 (Figure tein-replacement and regenerative medicine 9. 1). Overcoming delivery of RNAs across the lipid mRNA-based protein replacement therapies are bilayer and into cells remains a major challenge 3. used to replace proteins in vivo that are not Furthermore, once internalised, the endocytic expressed/expressed at a low level or are non-func - pathway – a major cellular active uptake mecha - tional using IVT mRNA. mRNA cancer nism for agents too large to permeate passively – immunotherapy agents are at advanced stages of leads to entrapment in the endosome and subse - development ( Table 1 ), with first in man trials quent degradation in the lysosome. For example, under way for mRNA vaccines including only 0.1% to 2% of siRNAs evade degradation Rocapuldencel-T (Argos Therapeutics Inc) and BI- and reach the RNAi machinery in the cytosol. New 1361849 (Boehringer Ingelheim GmbH). in vivo RNA delivery technologies including LNP or PNP systems and the use of aptamer or Antisense RNA conjugation have overcome some of the challenges Most current antisense RNAs have been developed associated with delivery of RNA-based therapeu - from sequences complementary to the target tics, with the selection of the delivery system mRNA, and are introduced into cells to reduce or depending on the therapeutics properties, type of modify expression of the protein upon binding to target cell and desired delivery route. For example, mRNA to alleviate the symptoms of the disease. LNPs tend to end up in the liver, which has been Sequence-specific antisense RNAs inhibit gene exploited at Alnylam Pharmaceuticals, Dicerna expression by altering mRNA splicing, arresting Pharmaceuticals and Arrowhead Pharmaceuticals mRNA and inducing mRNA degrada - Inc by attaching N-acetylgalactosamine (GalNAc) tion by ribonucleases (RNase H). Previously, natural to siRNAs to specifically target the hepatic asialo - antisense RNAs were evaluated for gene silencing, glycoprotein receptor on liver cells and trigger however, their inherent instability led to the develop - internalisation. Improving endosome escape is ment of modified antisense RNAs that are either another key step. The most common approaches more resistant but still activate RNase H or

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Figure 1 Delivery and mechanism of action for different classes of RNA-based therapeutics. RNA-based therapeutics including mRNA, siRNA, miRNA and antisense RNA, represented here as magenta rods, can be delivered via non- specific uptake using lipid nanoparticle (LNP) and polymer systems, or via receptor-mediated uptake using aptamer-, N-Acetyl-D- galactosamine (GalNAc)- or antibody-conjugate systems. Following endosome escape, single-stranded IVT mRNA can replace proteins in vivo that are not expressed/expressed at low level or are non- functional, whereas single- stranded antisense RNA or double-stranded RNAi therapeutics (miRNA and siRNA) attenuate or abolish protein production. Furthermore, RNA aptamers can block protein-protein or receptor-ligand interactions, disrupting the function of the target protein

bind to RNA without activating RNase H. Modified siRNAs to silence gene expression through post- antisense RNAs exhibit significantly-improved tis - translational gene silencing or transcriptional sue half-life and prolonged inhibitory activity. To silencing. Double-stranded miRNAs and siRNAs date, two antisense RNA drugs have gained FDA bind to mRNA and inhibit protein translation. approval: Spinraza (Biogen Inc) and Exondys 51 Endogenous miRNAs induce translational repres - (Sarepta Therapeutics Inc) ( Table 1 ). sion and mRNA degradation when the antisense strand displays limited complementarity to the tar - RNAi: miRNA and siRNA get mRNA, whereas sequence-specific cleavage is The cellular process of RNAi utilises miRNAs and exploited by exogenous siRNAs that display perfect

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or near-perfect base pairing with the mRNA target nanoparticle carriers allow for slow drug release References (Figure 1 ). within the cell to regulate dose. Patisiran (brand 1 Crooke, ST, Witztum, JL, name Onpattro; Alnylam Pharmaceuticals Inc) Baker, BF. RNA-targeted therapeutics. Cell Metabolism. miRNA represents the first FDA approval of an RNAi ther - 2018; 27: 714-739. miRNAs are small non-coding RNAs that play key apeutic in an LNP formulation for hereditary 2 Burnett, JC and Rossi, JJ. roles in cell differentiation, proliferation and sur - transthyretin-mediated amyloidosis (hATTR) in RNA-based Therapeutics- vival. The dysregulation of endogenous miRNAs adults (FDA approved in August 2018; Table 1 ). Current Progress and Future occurs in multiple diseases including hepatitis, car - Prospects. Chem Biol. 2012;19(1): 60-71. diovascular diseases and cancer (where miRNAs RNA aptamers 3 Dowdy, SF. Overcoming act as tumour suppressors or oncogenes). miRNAs RNA aptamers are short, single-stranded RNAs cellular barriers for RNA are loaded on to the RNA-induced silencing com - that are usually selected in vivo to bind to specific therapeutics. plex (RISC) and interact with partially comple - molecular targets using SELEX (systematic evolu - Biotechnology. 2017; 35(3): mentary targets on mRNA to suppress protein tion of ligands by exponential enrichment). RNA 222-229. 4 Kulkarni, JA, Cullis, PR and expression ( Figure 1 ). Antisense RNAs comple - aptamers have a propensity to form complementary van der Meel R. Lipid mentary to miRNA can block activity, whereas base pairs, which drives the formation of aptamer- Nanoparticles Enabling Gene double- or single-stranded RNAs that mimic target complexes. Aptamers feature the high affini - Therapies: From Concepts to miRNA can enhance activity. Both miRNA ty of antibodies but also offer several distinct Clinical Utility. Nucleic Acid inhibitors and mimics are currently being devel - advantages: their relatively small size and flexibility Ther. 2018;28(3):146-157. 5 Song, J and Yi, C. Chemical oped and have shown encouraging results 10 . For allow engagement with binding sites inaccessible to Modifications to RNA: A New example, RG-012 (Regulus Therapeutics Inc) is a larger antibodies; improved transport and tissue Layer of Gene Expression miRNA drug currently being evaluated in Phase I penetration; quick synthesis and comparatively Regulation. ACS Chem. Biol. trials for the treatment of Alport syndrome 11 . lower manufacturing costs; and high stability and 2017; 12 (2): 316-325. minimal immunogenicity. Many aptamers are inter - 6 Mauer, J, Luo, X, Blanjoie, A, Jiao, X, Grozhik, AV, Patil, DP, siRNA nalised upon binding to cell-specific receptors, Linder, B, Pickering, BF, Vasseur, In contrast to miRNAs, which attenuate protein making them useful drug carriers to deliver small- JJ, Chen, Q, Gross, SS, production, when an siRNA recognises mRNA it molecule chemotherapeutics, siRNAs, miRNAs or Elemento, O, Debart, F, causes cleavage and degradation of the mRNA and antisense RNAs into targeted tissues ( Figure 1 ). Kiledjian, M and Jaffrey, SR. completely silences the gene, shutting down pro - However, the inherent physiochemical characteris - Reversible methylation of m6A in the 5’ cap controls tein production ( Figure 1 ). siRNAs arose as a nat - tics of aptamers, which affect metabolic stability m mRNA stability. Nature. 2017; ural defence mechanism against RNA viruses and and limit in vivo potency, combined with a lack of 541(7637): 371-375. are double-stranded RNAs acting as prodrugs: the available safety data, have hindered their develop - 7 Johannes, L and Lucchino, M. antisense strand is pharmacologically active where - ment. As with other classes of RNA-based thera - Current Challenges in as the sense strand facilitates drug delivery, trans - peutics, unmodified aptamers are susceptible to Delivery and Cytosolic Translocation of Therapeutic porting the antisense strand to the intracellular nuclease-mediated degradation leading to very RNAs. Nucleic Acid Ther. (Ago) loading complex. There are four short in vivo half-lives (typically less than 10 min - 2018;28(3):178-193. Ago proteins that can be loaded with miRNAs or utes). Therefore, most aptamers in clinical develop - 8 Juliano, RL. The delivery of siRNAs and alter translation and/or RNA stability: ment feature chemical modifications to improve therapeutic oligonucleotides. siRNAs preferentially bind to Ago2. siRNAs can nuclease resistance and pharmacokinetic proper - Nucleic Acids Res. 2016; 44(14): 6518-6548. also compete with miRNAs loaded on to Ago2, ties 13 . For example, Macugen is PEGylated and 9 Sahin, U, Karikó, K and thereby altering the half-lives of other cellular conjugated to (PEG) to extend Türeci, Ö. mRNA-based RNAs. Exogenous siRNAs operate via a sequence- its half-life in vivo . therapeutics – developing a specific mechanism with perfect complementarity Aptamers can act as antagonists to block pro - new class of drugs. Nat Rev to the target mRNA but can also have miRNA-like tein-protein or receptor-ligand interactions; as ago - Drug Discov. 2014;13(10): 759-780. effects on some partially complementary mRNA nists to activate receptors; or as cell-specific deliv - 10 Rupaimoole, R and Slack, sequences, leading to a lack of specificity. ery systems. All aptamers currently in clinical FJ. MicroRNA therapeutics: Therefore, a single siRNA sequence can potentially development are inhibitors that disrupt the func - towards a new era for the modulate expression of hundreds of off-target tion of a target protein. In addition, aptamers can management of cancer and genes, which can impact on the efficacy of the be designed to act as RNA decoys that compete other diseases. Nat Rev Drug Discov. 2017; 16(3):203-222. RNA drug. with a natural RNA sequence that represents the 11 A Study of RG-012 in Following systemic injection, siRNAs encapsu - target of an RNA-binding protein, sequestering its Subjects With Alport lated in LNPs often tend to accumulate in the liver interaction. In December 2004, Macugen Syndrome. Available from: and spleen 12 . For systematic delivery, synthetic car - (Pfizer/Valeant Pharmaceuticals International Inc), https://clinicaltrials.gov/ct2/sho riers are usually decorated with cell-specific ligands a VEGF-specific modified RNA aptamer, gained w/NCT03373786. or aptamers that facilitate receptor-mediated FDA approval for the treatment of age-related uptake ( Figure 1 ). Furthermore, biodegradable (AMD) and several other Continued on page 23

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RNA-based aptamers or decoys have entered clini - Number of companies working on RNA cal development ( Table 1 ). therapeutics in clinical development Emerging technologies New technologies and modalities to target RNA include the application of the CRISPR-Cas9 genome editing technology, DNA-directed RNA interference (ddRNAi) technology, and the devel - opment of selective small-molecule modulators of RNA or RNA-modifying enzymes 14 . For example, CAL-1, Calimmune’s lead therapeutic candidate, represents an RNA-based gene therapy using ddRNAi to silence the CCR5 gene to control HIV mRNA Antisense RNA miRNA siRNA RNA aptamer infection and to protect individuals with HIV from developing AIDS. Several companies that focus on Graph 1: Companies developing RNA-based therapeutics in the clinic (as of July 2018). Data the development of small-molecule RNA modula - provided by GlobalData Plc tors have been established in recent years. For example, Expansion Therapeutics Inc (San Diego, California, USA) has developed a platform to iden - tify small molecules interacting with RNA Number of clinical trials by RNA therapeutic class (SMiRNA™), including mRNA and various non- coding RNAs, across multiple therapeutic areas. In addition, STORM Therapeutics (Cambridge, UK) specialises in RNA epigenetics, and the develop - ment of small-molecule inhibitors of RNA-modify - ing enzymes for the treatment of cancer. Targeting splice-variant control sequences within introns (non-coding regions of an RNA transcript or DNA sequence within a gene) or exons (coding regions) offers further opportunities to develop mRNA Antisense RNA miRNA siRNA RNA aptamer therapeutics. For example, Skyhawk Therapeutics Inc (Waltham, Massachusetts, USA), was founded Graph 2: Number of RNA-based therapeutics in clinical trials (as of July 2018). Data this year with a platform to identify selective small- provided by GlobalData Plc molecule modulators of the RNA spliceosome complex that target RNA mis-splicing (exon skip - ping), which drives multiple diseases including neu - rological conditions and cancer. These emerging Forecast drug sales technologies offer great opportunities to develop alternative strategies to target RNA for drug devel - opment.

Marketplace The first notable success for RNA-based therapeu - tics was the FDA approval of the RNA aptamer, Macugen (Pfizer/Valeant Pharmaceuticals International Inc), for the treatment of AMD in December 2004. Since then, two antisense RNAs and one siRNA have gained FDA approval: Exondys 51 (approved in September 2016; Sarepta Therapeutics Inc) is used to treat Duchenne muscu - lar dystrophy; Spinraza (December 2016; Biogen Inc) represents the first approved drug for the treatment of spinal muscular atrophy in children Graph 3: Forecasted global sales for RNA-based therapeutics from 2016-24. Revenue is and adults; Onpattro (August 2018; Alnylam given in US$m. Data provided by GlobalData Plc Pharmaceuticals Inc) represents the first FDA

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approval of an RNAi therapeutic for hATTR in have successfully made it through to market and Continued from page 21 adults. As of July 2018, 69 companies are actively several other RNA agents are currently in clinical developing mRNA, antisense RNA, RNAi or RNA programmes. In addition, new screening tools are 12 Zhao, Y and Huang, L. Lipid nanoparticles for gene aptamer therapeutics ( Graph 1 ) with 315 ongoing making it easier to identify disease-associated RNA delivery. Adv Genet. 2014; clinical trials ( Graph 2 ). Table 1 highlights the sequences to target. To date, drug discovery efforts 88: 13-36. major RNA drugs in five or more clinical trials and have primarily focused on mRNAs, silencing gene 13 Zhou, J and Rossi, J. their current highest development stage. expression using antisense RNAs and siRNAs, or Aptamers as targeted Furthermore, the forecast global sales for RNA- developing RNA aptamers that bind to specific therapeutics: current potential and challenges. Nat Rev Drug based therapeutics is expected to exceed US$10 bil - molecular targets. Emerging technologies and Discov. 2017; 16(3):181-202. lion by 2024 (based on an analysis carried out modalities, including CRISPR-Cas9 genome edit - 14 Chakradhar, S. Bringing using the GlobalData Plc database ( Graph 3 ). ing and small-molecule modulators of RNA or RNA into the fold: Small The market has recently witnessed several strate - RNA-modifying enzymes, offer further opportuni - molecules find new targets in gic collaborations and partnerships between big ties to target mRNA for drug discovery. Future RNA to combat disease. Nat Med. 2017; 23(5): 532-534. Pharma and Biotech companies, which leverage advances in RNA therapeutic design and delivery proprietary technology platforms. For example, technologies will help exploit the full commercial (Cambridge, USA) has established a potential of RNA-based therapeutics. number of strategic partnerships to advance mRNA medicines. In April 2018, Arbutus Acknowledgements Biopharma Corporation, which has proprietary We would like to thank Ajay Karandikar at LNP and ligand-conjugate delivery technologies, GlobalData Plc for help with database searches, and Roivant Sciences entered into an agreement to Peter Turnbull for assistance with Figure 1 graph - launch Genevant Sciences (Burnaby, Canada) – a ics, and Drs Annette Bak and Sara Richardson at jointly-owned company aiming to develop and AstraZeneca (Gothenburg, Sweden) and Dr Neil commercialise a range of RNA therapeutics target - Jones at CRUK-TDL (London, UK) for critically ing genetic disorders with limited or no treatment reviewing this article and for providing construc - options available. Genevant plans to develop prod - tive feedback. DDW ucts both in-house and in industrial partnerships across RNAi, mRNA and gene editing modalities with the goal of delivering between five and 10 RNA programmes to the clinic by 2020. Recently (in August 2018), BioNTech AG entered into a multi-year research and development collaboration Dr Xiaoqiu Wu is associate principal scientist at with Pfizer to jointly develop mRNA-based AstraZeneca (Gothenburg, Sweden) in the influenza vaccines. These new and exciting strate - Pharmaceutical Sciences iMed Biotech Unit where gic collaborations and partnerships will potentially she is involved in developing methods for new lead to ground-breaking developments in the modalities including mRNA formulation and anal - RNA-based therapeutics field. ysis. Xiaoqiu obtained a PhD in Medical Biochemistry from the Karolinska Institutet, Outlook Sweden, and postdoctoral research at the RNA-based therapeutics offer opportunities for Structural Genomics Consortium at Oxford Biotech and Pharma companies to go beyond their University. Subsequently, she worked at several existing repertoire of small-molecule and antibody Biotech companies in Sweden including IMED AB, portfolios. However, the development of RNA- Etvax and Alligator Bioscience AB. based therapeutics is challenging since RNA is inherently unstable and prone to degradation, is Dr Andrew P. Turnbull is senior principal scientist immunogenic and rapidly cleared and requires safe at CRUK Therapeutic Discovery Laboratories and effective delivery. The use of RNA modifica - (CRUK-TDL) where he established protein crys - tions to enhance stability and improved synthetic tallography. Previously, he was team leader in the delivery carriers, such as nanoparticle systems, X-ray crystallography group at the Structural have helped overcome some of these development Genomics Consortium at Oxford University and, hurdles. However, delivery across the lipid bilayer prior to that, worked at the Protein Structure remains a significant challenge and approaches to Factory in Berlin in the high-throughput crystal enhance endosomal escape of RNA drugs are structure analysis unit located at the BESSY syn - required. To date, four RNA-based drugs – chrotron source. Andrew obtained a PhD in Macugen, Exondys 51, Spinraza and Onpattro – Biochemistry from the University of Sheffield.

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