WO2016180784A1 - Improved treatments using oligonucleotides - Google Patents

Abstract

Potential side effects of unintentional activation of platelets by phosphorothioated oligonucleotides are minimised in various ways, including a combination therapy, wherein PS-ONs are combined, in one composition, a kit-of-parts, and/or in a combination therapy regime, with either or both specific platelet activation pathway inhibitors, and/or the common platelet aggregation pathway.

Description

IMPROVED TREATMENTS USING OLIGONUCLEOTIDES

FIELD OF THE INVENTION

The present invention relates to the field of medicine, more in particular of combination therapy involving oligonucleotides.

BACKGROUND OF THE INVENTION

The use of oligonucleotides in medicine has rapidly evolved over the last two decades. Oligonucleotides are being used, for example, to interfere with gene expression, by up-regulating or down-regulating genes involved in the disease pathway on the level of transcription, pre- mRNA splicing or translation. In addition, oligonucleotides are being used to reverse genetic mutations at the DNA or RNA level, by oligonucleotide-guided repair. It is now possible to alter the symptoms or the severity of a host of genetic diseases by directly interfering with the genetic cause of disease, be it at the DNA or at the RNA level. The recent successes of oligonucleotide- based therapies is in part attributable to chemical modifications that increase the affinity of the ON for its target and/or that protect the ONs against degradation by nucleases. One chemical modification that has particularly contributed to the widespread use of ONs in today's medicine is the modification of the backbone of the ON, normally consisting of phosphodiester internucleosidic linkages, by exchanging one, or two, non-linking oxygens in backbone of the ON. Nowadays, mono-thio (PS-) and di-thio (PS2) modified oligodeoxyribonucleotides and oligoribonucleotides are routinely used for medicinal use in humans.

Relatively recently, it has been reported that a fully phosphorothioated oligodeoxynucleotide (ODN) administered intravenously was capable of activating blood platelets through platelet-specific receptor glycoprotein VI (GPVI), thereby mediating platelet aggregation and thrombus formation in vitro, in an in vivo mouse model (a murine carotid artery ferric chloride model, described on page 133, left col. ultimate paragraph, in Flierl et al., supra), as well as in mice (Flierl et al. J. Exp. Med. 2015 Vol. 212 No. 2, 129-137). The activation of platelets was reported to be sequence independent and to require PS-modification. Several tests pointed to glycoprotein VI (GPVI) as the receptor for the PS-modified oligodeoxyribonucleotide ODN2395. A function blocking anti-GPVI antibody prevented ODN2395 -induced platelet aggregation. The authors postulate a potential mechanism of interference between the PS- modified ODN and GPVI, by explaining that the poly-anionic PS-backbone is electrostatically attracted to a sequence of positively charged amino acids in a groove of the collagen binding domain of GPVI.

The authors advise that appropriate hematological tests should be developed to monitor these platelet-activating effects during clinical trials. Moreover, the authors conclude that their findings support the development of alternative chemical modifications to provide nuclease resistance for nucleotide-based therapeutics. SUMMARY OF THE INVENTION

The present inventors, being aware of the potential side effects of unintentional activation of platelets by phosphorothioated oligonucleotides, propose an alternative solution to deal with these potential side effects. Accordingly, solutions are provided, including a combination therapy, wherein PS-ONs are combined, in one composition, a kit-of-parts, and/or in a combination therapy regime, with either or both specific platelet activation pathway inhibitors, and/or the common platelet aggregation pathway.

The solutions offered are not limited to PS-ONs. ONs of different chemistry but with similar characteristics as PS-ONs in terms of platelet activation, aggregation and/or initiation or stimulation of thrombus formation may benefit from some of the proposed solutions just the same.

Thus the invention provides a method for the treatment of an individual in need thereof with an oligonucleotide (ON) to treat or prevent a disease, wherein the ON is capable of causing platelet activation, platelet aggregation and/or thrombus formation at a ON blood plasma concentration of between about 0.01 and 10 μΜ, characterized in that a countermeasure is taken to reduce such platelet activation, aggregation and/or thrombus formation, and/or any side effects thereof. Such countermeasures are discussed below in more detail.

The invention also provides a pharmaceutical composition or a kit of parts comprising: (A) an ON capable of causing platelet activation, platelet aggregation and/or thrombus formation in an individual to be treated, at a ON blood plasma concentration of between about 0.01 and 10 μΜ, and (B) an inhibitor of platelet activation, aggregation or thrombus formation selected from the group consisting of: (i) an inhibitor of collagen (platelet-specific) collagen-receptor interaction, such as an antibody (e.g. anti-GPVI antibody JAQ1) (ii) a COX 1 -inhibitor (e.g. acetylsalicylic acid or a pharmaceutically acceptable salt thereof, or a carbasalate salt); (iii) an inhibitor of the ADP - P2Y12 interaction (iv) an inhibitor of the fibrinogen-GPIIb/IIIa interaction; (v) a NOX- inhibitor, such as NOX1 -inhibitor ML171 , apocynin, or 2 acetylphenothiazine; (vi) an antioxidant, such as vitamin C or diferuloylmethane, or a combination of one or more of (i) to (vi) above.

The invention also provides a method for modifying a first therapeutic oligonucleotide to give a second therapeutic oligonucleotide, wherein (a) the first therapeutic oligonucleotide binds to a target nucleic acid, includes one or more phosphorothioate linkages, and causes platelet activation, platelet aggregation and/or thrombus formation; and (b) the second therapeutic oligonucleotide binds to the target nucleic acid, includes one or more phosphorothioate linkages, and causes less platelet activation, platelet aggregation and/or thrombus formation than the first therapeutic oligonucleotide, wherein the method comprises one or more of the following: (i) where the first therapeutic oligonucleotide is 18 or more nucleotides long, reducing its length to give a second therapeutic oligonucleotide which is less than 18 nucleotides long; (ii) reducing the total number of phosphorothioate linkages, such that the second therapeutic oligonucleotide has fewer phosphorothioate linkages than the first therapeutic oligonucleotide; and/or (iii) reducing the number of consecutive phosphorothioate linkages, such that the second therapeutic oligonucleotide has fewer consecutive phosphorothioate linkages than the first therapeutic oligonucleotide.

The invention also provides a method for producing an oligonucleotide specific for a target nucleic acid, comprising steps of: (a) preparing a first therapeutic oligonucleotide which binds to a target nucleic acid, includes one or more phosphorothioate linkages; (b) determining the first therapeutic oligonucleotide's ability to cause platelet activation, platelet aggregation and/or thrombus formation; (c) preparing a second therapeutic oligonucleotide which also binds to the target nucleic acid and includes one or more phosphorothioate linkages; (d) determining the second therapeutic oligonucleotide's ability to cause platelet activation, platelet aggregation and/or thrombus formation; and (e) if the second therapeutic oligonucleotide has a lower ability to cause platelet activation, platelet aggregation and/or thrombus formation than the first therapeutic oligonucleotide, synthesizing and purifying the second therapeutic oligonucleotide for use as a pharmaceutical. Step (b) and (d) will generally be assessed by the same criteria, and suitable assays are known e.g. a reduction of OD5 5nm over time, upon incubation of platelet rich plasma in the presence of said oligonucleotides in an in vitro assay.

DETAILED DESCRIPTION OF THE INVENTION

Role of platelets in haematological disorders

Blood platelets in circulation are kept in an inactive state by nitric oxide and prostacyclin, that are released by endothelial cells lining the blood vessels. Certain signals can activate platelets, subsequently triggering a cascade of activities that cause platelets to aggregate and, through interaction with fibrinogen, form thrombi that stop bleeding in case of damage to the vasculature. Endothelial cells produce adenosine diphosphatases (ADPase) on their surface, which in addition to NO and prostacyclin, serve to keep the platelets in check by degrading adenosine diphosphate (ADP) released by activated platelets. In case of damage to blood vessels, the sub-endothelial matrix, comprising among other things collagen, von Willebrand factor (vWF) and fibronectin, becomes exposed and though interaction of these factors with receptors on the platelet cell surface, cause platelet adherence and secretion of factors that subsequently cause platelet activation.

Basically, two distinct initial - specific - activation pathways are recognized. The first activation pathway is induced by collagen, causing platelet adhesion and secretion of Thromboxane A2 (TXA2), which in turn causes platelet recruitment and, in the last step referred to as the common pathway involving binding of fibrinogen to GPIIb/III, to platelet aggregation and thrombus formation.

The second initial - specific - pathway is mediated by vWF, which in addition to platelet adhesion induces secretion of ADP. ADP also causes recruitment and activation of platelets, and - through activation of the common pathway involving fibrinogen binding to GPIIb/GPIIIa - causes platelets aggregation.

The hallmark of the first platelet activation pathway, is the production of Thromboxane A2, through the prostaglandin G/H synthesis pathway, which involves cyclooxygenase-1 (COX-1). This pathway can be blocked by acetylsalicylic acid (Aspirin) and similar salts, such as carbasalate calcium (Ascal). Aspirin and its likes, acetylate serine residue 529 of COX-1, thereby irreversibly preventing the synthesis of TXA2, which in turn blocks this specific activation pathway.

The other specific platelet activation pathway, involving vWF and ADP secretion, can be inhibited by Ticlopidine and Clopidogrel, which block P2Y12, a key ADP receptor.

The common pathway, involving binding of fibrinogen to GPIIb/GPIIIa, can be blocked by monoclonal antibody Abciximab, eptifibatide, or tirofiban.

Reactive oxygen species, such as superoxide anions, hydrogen peroxide, hydroxyl radicals and peroxynitrite, produced by activated platelets, seem to be required for full platelet activation. The presence of antioxidants or NADPH-oxidase (NOX) inhibitors prevent full aggregation capacity of platelets (Krotz et al, Blood 2002, 100(3); 917-924; Pignatelli P et al, Blood 1998; 91(2), 484-490; Pratico D. et al, Circulation 1999; (24), 3118-3124, as cited in Walsh T.G. Redox. Biol. 2014(2), 178-186). In particular, NADPH-oxidase 1 forms an attractive target for platelet activation intervention using antioxidants, such as apocynin or ML171. Conceivably, natural antioxidants such as vitamin C, diferuloylmethane (also known as curcumin, the active ingredient of turmeric, Curcuma longa), may be used to prevent or mitigate the platelet activation stimulating effect of phosphorothioated ONs.

Another finding by Walsh et al. {supra) suggests that it should be possible to design ONs that are less likely to induce platelets, either due to their length (even full phosphorothioated ONs of less than 17 consecutive nucleotides are poor platelet activators) and/or different phosphorothioation pattern, for example by avoiding 9 or more, preferably 8 or more, 7 or more, 6 or more, 5 or more, 4 or more, 3 or more or 2 consecutive PS linkages in the backbone of the oligonucleotide. Hence, phosphorothioated ONs according to the invention may comprise any regular pattern of phosphorothioation, such as alternating PS and PO internucleosidic linkages (PS-PO)n, wherein PS may be a mono- or dithio-substituted phosphate group and PO is a regular phosphate group, or a regular pattern represented by the general formula ((PS)_n-PO_m))k, wherein n is an integer between 1 and 9 (inclusive) and m is an integer between 1 and 9 (inclusive) and k is an integer between 1 and 50, and wherein the total number of internucleosidic linkages k*(n+m) is between 12 and 100. Phosphorothioated ONs according to the invention may also comprise an irregular pattern of PS and PO linkages, such that the proportion of PS linkages is less than 95%, preferably less than 90%, less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%), 40%), 35%) or 30%>, as long as the stability of the ONs is not entirely abolished. According to the invention also envisaged is the use of such partially phosphorothioated ONs in the treatment of disease in humans in order to reduce the risk of unintended platelet aggregation induced side effects, especially in humans bearing an increased risk of platelet induced disorders. Humans bearing an increased risk of such disorders, may be genetically predisposed to develop such disorders, be predisposed to develop or suffer from such a disorder due to life-style or age, or any other reason. Examples of such disorders are deep vein thrombosis, lung embolisms, temporary ischemic attacks, heart failure, myocardial infarction, stroke, and cardiovascular attack in general. Indicators of increased risk are well known to practitioners in the field of internal medicine, cardiology and neurology. A familial history of high cholesterol, high blood pressure, myocardial infarctions, strokes, atherosclerosis, vascular dementia, may be indicators that a person bears an increased risk of developing a platelet aggregation induced disorder that may be further induced by the use of phosphorothioated ONs. The prolonged, or chronic use of PS ONs, depending on the dose and administration regime, may pose risks to individuals that are not generally bearing an increased risk of platelet aggregation induced disorders. Also for those individuals, the compositions or combination therapy regimens may be of advantage. Accordingly, phosphorothioated ONs having a reduced number of PS internucleosidic linkages compared to a fully phosphorothioated ON of the same length, for prolonged or chronic use to treat or prevent disease in humans not bearing an increased risk to develop a platelet aggregation induced disorder is also encompassed by the present invention.

The invention also envisages combination of a particular ON design, such as shorter than 17 nucleotides and/or a reduced number of PS internucleosidic linkages compared to a fully phosphorothioated ON of the same length (as described herein), in combination with the use of inhibitors of platelet activation, platelet aggregation and/or thrombus formation for use in the treatment of disease in humans.

In a first aspect according to the invention a composition is provided, comprising an oligonucleotide comprising a plurality of thio-substituted internucleosidic linkages and platelet activation or aggregation inhibitor/selected from the group consisting of (i) an inhibitor of collagen (platelet-specific) collagen-receptor interaction, such as antibodies (e.g. anti-GPVI antibody JAQ1) (ii) a COX 1 -inhibitor (e.g. acetylsalicylic acid or a pharmaceutically acceptable salt thereof, or a carbasalate salt); (iii) an inhibitor of the ADP - P2Y12 interaction (iv) an inhibitor of the fibrinogen-GPIIb/IIIa interaction; (v) a NOX-inhibitor (e.g. the commercially available NOX1 -inhibitor ML171 or apocynin (both described in Walsh et al. supra), 2- acetylphenothiazine (Vara D. et al, Br. J. Pharmacol. 2013; 168(1), 212-224); (vi) antioxidants (e.g. vitamin C or diferuloylmethane, the active ingredient of turmeric), or a combination of one or more of the above.

The ON comprising a plurality of thio-substituted internucleosidic linkages may be one comprising a regular pattern of phosphorothioated and phosphate internucleosidic linkages as described above, or an irregular pattern, such that the PS proportion is less than 95%, preferably less than 90%, less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35% or 30% of the total number of inter-nucleoside PS linkages. Care should be taken that the stability of ON against nucleases (which is enhanced relative to PO linkages by the presence of PS) is not entirely abolished as a consequence of the limitation of the number of PS-linkages.

In a second aspect, fully phosphorothioated ONs, or partially phosphorothioated ONs having a reduced platelet activation effect relative to their fully phosphorothioated counterparts, are used in combination with an inhibitor of platelet activation, aggregation or thrombus formation, either in a single composition, or as a kit of parts, or in a treatment regimen involving separate administration of the ON to a patient in need and the inhibitor of platelet activation, aggregation or thrombus formation.

Combination therapy may comprise any combination of a reduced PS-linkage ON as described herein and an inhibitor of platelet activation, platelet aggregation and/or thrombus formation, as described herein, in any order, or simultaneously, by any mode of administration, which may be the same or different for the ON and the inhibitor, at any dosage or treatment regime. For example the ON may be administered prior to, simultaneously or subsequent to the platelet inhibitor, through injection (intravenously, subcutaneously, intradermally, intraocularly, intramuscularly, intra-cerebrally, and the like), through inhalation using a nebulizer or spray, intra-nasally, topically in a spray, oil or ointment, orally in the form of a powder, liquid or pill, rectally, etc. Similarly, the platelet inhibitor may be administered in any form using any pharmaceutically and clinically acceptable route of administration, including any of the above mentioned routes of administration. Usually, oral presentations of the inhibitors, in the form of tablets, capsules or powders are preferred.

Treatment regimes will vary widely, depending among other things on the genetic disease treated with the ON, the target population, the severity of the disease, the time of onset of the disease, the therapeutic target molecule of the disease (e.g. DNA or RNA), the mode of action of ON, the route of administration, the dosage, the unintended side effects, and the like. The treatment regime of the ON and the inhibitor may be the same, similar or widely differing. For example the ON treatment regime may be once daily, once weekly, once monthly, once quarterly or once yearly, during a limited period of time or chronic, e.g. during the life-time of the patient, or anything in between once and life-long. Therapy aimed at making a reversal of a genetic mutation on the DNA level may require fewer administrations of the ON than therapies aimed at a reversal on the RNA level. Those of skill in the art will appreciate that whereas the regimens for the ONs may vary widely due to the desired therapeutic effect on the disease symptoms, the regime for the inhibitors is aimed at reducing the unintended side effects caused by the ONs. Hence, it is generally advisable to ensure that whenever the effect of the ONs on platelet activation, aggregation or thrombus formation exist, the effect of the inhibitor should be present. This does not mean that the inhibitor itself must be present during such time. For example, acetylsalicylic acid, or its salts, exert their platelet aggregation inhibitory effect by acetylating a serine residue in the enzyme (COX-1) responsible for the conversion of arachidonic acid into prostaglandin G/H2, a key step in the production of thromboxane A2, responsible for platelet activation and inducing the common platelet aggregation pathway. Since platelets are unable to synthesize proteins as they lack the necessary biochemical machinery, the serine acetyl ation of the COX-1 enzyme leads to a rapid and irreversible phenotypic change of the circulating platelets, which lasts for as long as the platelets live - between 9 and 11 days. The half-life of aspirin, however, is only about 20 minutes. Hence, long after the inhibitor, aspirin in this case, is cleared from the blood stream, its effect on the inhibition of platelet activation remains present. This example illustrates, that the treatment regimen of the inhibitor is not only dependent on the treatment regimen of the ON, but also on the pharmacodynamics of the inhibitor itself.

In the case of acetylsalicylic acid, or its pharmaceutical salts (readily available under the trademarks Aspirin and Ascal), a daily dose of 75 - 100 mg, is usually recommended for individuals at risk of developing arterial blood clots, the main cause of temporary ischemic attacks, myocardial infarction and other forms of cardiovascular attacks in these patients. Similar doses, administered once daily, should be sufficient to protect individuals not bearing an increased risk of such cardiovascular disorders as mentioned above but under treatment with PS ONs that have the potential of inducing platelet activation. It would be preferably to maintain the individual on inhibitor treatment for as long as the ONs circulate in the individuals blood stream and are capable of inducing platelet activation and/or aggregation. Blood levels of fully phosphorothioated oligonucleotides of 18 nucleotides in length or longer that pose a potential risk of inducing platelet induced cardiovascular disorders, such as thrombus formation, lung embolisms, TIAs or other cardiovascular adverse events, are estimated to be in the range of 0.1 μΜ or higher. From literature data we know that, in mice treated to attain plasma levels of 1 μΜ ODN2395 (Flierl et al. supra) significant effects on platelet activation, aggregation and thrombus formation have been observed. Oblimersen, one of the best studied PS ONs in human clinical trials, in development for chronic lymphocytic leukemia (Advani et al., 2011 Expert Opin. Drug. Metab. Toxicol. 7:765-774) reaches levels of between 0.5 and 1.5 μΜ in blood, upon continuous i.v. administration of 7 mg/kg. Although no severe thromboembolic events have been reported for oblimersen so far, side effects have been reported including pyrexia, hypotension and thrombocytopenia.

In accordance with the invention, it is therefore recommended to monitor blood levels of PS-ONs used to treat humans and to provide inhibitor treatment whenever blood levels of phosphorothioated ONs in treated individuals reach values above about 1 μΜ, preferably above about 0.5 μΜ, still more preferably above about 0.1 μΜ. When ONs are being used that comprise fewer PS linkages than fully phosphorothioated ONs of the same length, provided they establish less efficient platelet activation in a test, the blood levels that would otherwise have prompted inhibitor treatment may be lowered accordingly.

Suitable regimens for the use of inhibitors of platelet activation, aggregation and thrombus formation, to protect patients treated with PS ONs having the capacity of inducing platelet activation and aggregation, should be worked out by physicians skilled in the art, such as cardiologist and neurologists, on a treatment by treatment and inhibitor by inhibitor basis, using the guidelines described herein.

Hence the present invention can conveniently be used in combination with any ON that is, or will be, used to treat human disease, wherein the ON has the capacity, either after single use or prolonged use, to induce platelet activation, aggregation and/or thrombus formation, in a human individual. The use of inhibitors of platelet activation, aggregation, or thrombus formation, to prevent or reduce the activation or aggregation of platelets, or thrombus formation, or to mitigate the side effects thereof, can also be combined with ONs that are not necessarily phosphorothioated but nevertheless have the capacity to induce platelet activation, aggregation or thrombus formation. In principle, all ONs that comprise a plurality of, preferably consecutive, internucleosidic linkages that are electrostatically attracted to a sequence of positively charged amino acids in a groove of the collagen binding domain of GPVI can suitably be combined in a regimen comprising inhibitors of platelet aggregation as disclosed herein, or be modified to reduce the effect of such (consecutive) internucleosidic linkages as described below. For ONs that comprise a plurality of PS-linkages in their backbone, preferably wherein all internucleosidic linkages of the ON are phosphorothioated ("fully phosphorothioated" ONs) the solution is to reduce the number of PS-linkages, randomly, or in an orderly fashion, such as by preventing 3, 4, 5, 6, 7 or 8 consecutive PS-linkages, as described herein, or the use of inhibitors of platelet activation, aggregation or thrombus formation, or a combination of both, may be used.

The solutions according to the invention are not limited to treatment of any particular disease, as long as ONs are involved. Examples of diseases that are, or can be treated using ONs that have the capacity to induce activation or aggregation of platelets, and/or thrombus formation are disorders, such as albinism, alpha- 1 -antitrypsin deficiency, Alzheimer disease, Amyotrophic lateral sclerosis, Asthma, β-thalassemia, Cadasil syndrome, Charcot-Marie-Tooth disease, Chronic Obstructive Pulmonary Disease (COPD), Distal Spinal Muscular Atrophy (DSMA), Duchenne/Becker muscular dystrophy, Dystrophic Epidermolysis bullosa, Fabry disease, Familial Adenomatous, fascioscapulo humeral dystrophy, Polyposis, Friedreich's ataxia, Galactosemia, Gaucher' s Disease, Glucose-6-phosphate dehydrogenase, Haemophilia, Hereditary Hematochromatosis, Hunter Syndrome, Huntington's disease, Hurler Syndrome, Inflammatory Bowel Disease (IBD), Inherited polyagglutination syndrome, Lesch-Nyhan syndrome, Lynch, Marfan syndrome, Mucopolysaccharidosis, Muscular Dystrophy, Myotonic dystrophy types I and II, Niemann-Pick disease type A, B and C, NY-esol related cancer, Parkinson's disease, Peutz-Jeghers Syndrome, Phenylketonuria, Pompe's disease, Primary Ciliary Disease, Pulmonary Hypertension, Retinitis Pigmentosa, Sandhoff Disease, Severe Combined Immune Deficiency Syndrome (SCID), Sickle Cell Anemia, Spinal Muscular Atrophy, Stargardt's Disease, Tay-Sachs Disease, tyrosinemia, X-linked immunodeficiency, various forms of cancer (e.g. BRCA1 and 2 linked breast cancer and ovarian cancer), and the like and they include the ONs mentioned in Table 1.

The phosphorothioated oligonucleotides that may require, or that benefit from, co- treatment with platelet aggregation inhibitors, according to the invention, can contain DNA-, RNA- or LNA nucleotides; there can be modified DNA-, RNA-or LNA-nucleotides present to enhance stability as described elsewhere herein. The oligonucleotide according to the invention may e.g. comprise an inosine and/or may comprise modified nucleotides, preferably selected from the group consisting of a 2'-0-alkyl ribose, 2'-0-methyl ribose, 2'-Fluoro ribose, methylphosphonate, PMO, 5-methyl-dC, 2-amino-dA, C5-pyrimidine. One such preferred example of a stabilized nucleotide is a 2'-0-methyl modified nucleotide, another example is a Locked Nucleic Acid (LNA) nucleotide.

A base modification includes a modified version of the natural purine and pyrimidine bases (e.g. adenine, uracil, guanine, cytosine, and thymine), such as hypoxanthine, orotic acid, agmatidine, lysidine, 2-thiopyrimidine (e.g. 2-thiouracil, 2-thiothymine), G-clamp and its derivatives, 5-substituted pyrimidine (e.g. 5-halouracil, 5-propynyluracil, 5-propynylcytosine, 5- aminomethyluracil, 5-hydroxymethyluracil, 5-aminomethylcytosine, 5-hydroxymethylcytosine, Super T), 7-deazaguanine, 7-deazaadenine, 7-aza-2,6-diaminopurine, 8-aza-7-deazaguanine, 8- aza-7-deazaadenine, 8-aza-7-deaza-2,6-diaminopurine, Super G, Super A, and N4-ethylcytosine, or derivatives thereof; N -cyclopentylguanine (cPent-G), N -cyclopentyl-2-aminopurine (cPent- AP), and N -propyl-2-aminopurine (Pr-AP), or derivatives thereof; and degenerate or universal bases, like 2,6-difluorotoluene or absent bases like abasic sites (e.g. 1-deoxyribose, 1 ,2- dideoxyribose, l-deoxy-2-O-methylribose; or pyrrolidine derivatives in which the ring oxygen has been replaced with nitrogen (azaribose)). Examples of derivatives of Super A, Super G and Super T can be found in US patent 6,683,173 (Epoch Biosciences), which is incorporated here entirely by reference. cPent-G, cPent-AP and Pr-AP were shown to reduce immunostimulatory effects when incorporated in siRNA (Peacock H. et al. J. Am. Chem. Soc. 2011, 133, 9200).

A sugar modification includes a modified version of the ribosyl moiety, such as -O- modified RNA such as 2'-O-alkyl or 2'-O-(substituted)alkyl e.g. 2'-0-methyl, T-0-(2- cyanoethyl), 2'-0-(2-methoxy)ethyl (2'-MOE), 2'-0-(2-thiomethyl)ethyl, 2'-O-butyryl, -O- propargyl, 2'-O-allyl, 2'-O-(2-amino)propyl, 2'-O-(2-(dimethylamino)propyl), 2'-O-(2- amino)ethyl, 2'-O-(2-(dimethylamino)ethyl); 2'-deoxy (DNA); 2'-O-(haloalkoxy)methyl (Arai K. et al. Bioorg. Med. Chem. 2011, 21, 6285) e.g. 2'-0-(2-chloroethoxy)methyl (MCEM), -O- (2,2-dichloroethoxy)methyl (DCEM); 2'-<3-alkoxycarbonyl e.g. T-0-[2- (methoxycarbonyl)ethyl] (MOCE), 2'-O-[2-(N-methylcarbamoyl)ethyl] (MCE), T-0-[2-(N,N- dimethylcarbamoyl)ethyl] (DCME); 2'-halo e.g. 2'-F, FANA (2'-F arabinosyl nucleic acid); carbasugar and azasugar modifications; 3 '-O-alkyl e.g. 3'-0-methyl, 3 '-0-butyryl, V-O- propargyl; and their derivatives. Another modification includes "bridged" or "bicylic" nucleic acid (BNA), e.g. locked nucleic acid (LNA), y/o-LNA, a-L-LNA, β-D-LNA, cEt (2'-O,4'-C constrained ethyl) LNA, cMOEt (2'-O,4'-C constrained methoxyethyl) LNA, ethylene-bridged nucleic acid (ENA), tricyclo DNA; unlocked nucleic acid (UNA); cyclohexenyl nucleic acid (CeNA), altriol nucleic acid (ANA), hexitol nucleic acid (ETNA), fluorinated ETNA (F-HNA), pyranosyl-RNA (p-RNA), 3'-deoxypyranosyl-DNA (p-DNA); morpholino (PMO), cationic morpholino (PMOPlus), PMO-X; and their derivatives. It is also encompassed by the invention to introduce more than one distinct sugar modification in an oligonucleotide according to the invention. BNA derivatives are for example described in WO 2011/097641, which is incorporated in its entirety by reference. Examples of PMO-X are described in WO2011/150408, which is incorporated here in its entirety by reference.

Preferred methods of treatment, kits and compositions according to the invention are those involving fully phosphorothioated ONs, especially those for intravenous use, as the ON concentrations in the blood for intravenously administered ONs are the highest for administration routes, all other parameters such as dose and dosing regimen being equal. Treatments that especially benefit from solutions according to the invention are those involving prolonged treatment and/or treatment with high dosages and/or those involving frequent dosing regimes and/or regimes involving intravenous administration. However, the invention is certainly not limited to any treatment regime, route of administration, dosage, disease, target population or oligo-chemistry. Any treatment involving ONs that have the capacity to induce platelet activation, aggregation and/or thrombus formation may benefit from a solution as described herein.

A non- limiting overview of ONs on the market or in development for treatment of mammalian, preferably human, disease, is provided in Table 1 below. Oligonucleotides can be prepared according to any method known in the art. The person skilled in the art knows how to synthesize the oligonucleotides.

A backbone modification other than phosphorothioation may be present in an ON requiring co-treatment with an inhibitor of platelet activation, aggregation or thrombus formation. Such other backbone modifications include phosphonoacetate (PACE), phosphonoacetamide (PACA), thiophosphonoacetate, thiophosphonoacetamide, H-phosphonate, methyl phosphonate, methyl phosphonothioate, methyl phosphate, ethyl phosphate, boranophosphate, methyl boranophosphate, methyl boranophosphonate, and their derivatives. Another modification includes phosphoramidite, phosphoramidate, N3'- P5' phosphoramidate, phosphordiamidate, phosphorothiodiamidate, sulfamate, dimethylenesulfoxide, sulfonate, triazole, oxalyl, carbamate, methyleneimino (MMI), and thioacetamido nucleic acid (TANA); and their derivatives. It is also encompassed by the invention to introduce more than one distinct backbone modification in an oligonucleotide.

Other chemical modifications of an oligonucleotide according to the invention include peptide-base nucleic acid (PNA), boron-cluster modified PNA, pyrrolidine-based oxy-peptide nucleic acid (POPNA), glycol- or glycerol-based nucleic acid (GNA), threose-based nucleic acid (TNA), acyclic threoninol-based nucleic acid (aTNA), morpholino-based oligonucleotide (PMO, PMO-X), cationic morpholino-based oligomers (PMOPlus), oligonucleotides with integrated bases and backbones (ONIBs), pyrrolidine-amide oligonucleotides (POMs) and their derivatives.

An oligonucleotide according to the invention preferably has a length of 15 to 100 nucleotides and is preferably 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or at least 40 nucleotides in length.

According to a preferred aspect of the invention a fully phosphorothioated oligoribonucleotide having the following sequence is used in combination treatment as described herein:

SEQ ID NO: 1; 5^*-AUCAUAGGAAACACCAAAGAUGAUAUUUUCUUU-3^* in which all ribonucleotide bases preferably are 2'-0-Me modified (see WO2014/011053).

The ON of SEQ ID NO: 1 ('QR-010') is being developed to treat CF patients having a dF08 mutation, via the airway. A nebulizer is preferably used for delivery of this ON in an aerosol to the airway epithelial cells. This ON is rapidly taken up into the blood stream in test mice and cynomolgus monkeys and, depending on the dose and the treatment regime, could reach blood levels that have the potential to induce platelet activation, aggregation and/or thrombus formation.

It is within the ambit of the invention to combine the treatment according to the invention with additional treatments that are, or may become, the standard of care for that disease, For example, in addition to the combinations proposed by the present invention, cystic fibrosis patients may used in combination with "mucus normalizers" such as a DNase, mannitol, hypertonic saline and/or antibiotics and/or a small molecule for treatment of CF, such as potentiator compounds for example Kalydeco (ivacaftor; VX-770), or corrector compounds, for example VX-809 (Lumacaftor) and/or VX-661.

To increase access to the target cells, Broncheo -Alveolar Lavage (BAL) could be applied to clean the lungs before administration of the oligonucleotides of SEQ ID NO: 1.

Preferably, in the embodiments of this aspect, the oligonucleotide of this aspect has a length of 15 - 100 nucleotides. More preferably, the length of the oligonucleotide is between 20 and 50, more preferably between 25 and 45 nucleotides, more preferably between 27 and 35 nucleotides, most preferably 33 nucleotides.

The invention is not limited to any particular administration form, presentation, or formulation, as long as the ON administered has the capacity to form critical blood concentrations that have been shown to induce platelet activation, aggregation or thrombus formation. For example excipients are commonly used in combination with ONs, that will (further) aid in enhancing the stability, solubility, absorption, bioavailability, activity, pharmacokinetics, pharmacodynamics and delivery of an oligonucleotide to the target tissues, in particular excipients capable of forming complexes, vesicles, nanoparticles, microparticles, nanotubes, nanogels, hydrogels, poloxamers or pluronics, polymersomes, colloids, microbubbles, vesicles, micelles, lipoplexes and/or liposomes, that deliver compound, substances and/or oligonucleotide(s) complexed or trapped in the vesicles or liposomes through a cell membrane. Examples of nanoparticles include gold nanoparticles, magnetic nanoparticles, silica nanoparticles, lipid nanoparticles, sugar particles, protein nanoparticles and peptide nanoparticles. Another group of nanoparticles are polymeric nanoparticles. Many of these polymeric substances are known in the art. Suitable substances comprise e.g. polyethylenimine (PEI), ExGen 500, polypropyleneimine (PPI), poly(2-hydroxypropylenimine (pHP)), dextran derivatives (e.g. polycations such like diethyl amino ethyl amino ethyl (DEAE)-dextran, which are well known as DNA transfection reagent can be combined with butylcyanoacrylate (PBCA) and hexylcyanoacrylate (PHCA) to formulate cationic nanoparticles that can deliver said compound across cell membranes into cells), butylcyanoacrylate (PBCA), hexylcyanoacrylate (PHCA), poly(lactic-co-gly colic acid) (PLGA), polyamines (e.g. spermine, spermidine, putrescine, cadaverine), chitosan, poly(amido amines) (PAMAM), poly(ester amine), polyvinyl ether, polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG) cyclodextrins, hyaluronic acid, colominic acid, and derivatives thereof), dendrimers (e.g. poly(amidoamine), lipids {e.g. 1,2- dioleoyl-3-dimethylammonium propane (DODAP), dioleoyldimethylammonium chloride (DODAC), phosphatidylcholine derivatives [e.g 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC)], lyso- phosphatidylcholine derivaties [ e.g. l-stearoyl-2-lyso-sn-glycero-3- phosphocholine (S- Ly soPC)], sphingomy eline, 2- { 3 - [bi s-(3 -amino-propyl)-amino] - propylamino } -N- ditetracedyl carbamoyl methylacetamide (RPR209120), phosphoglycerol derivatives [e.g. l,2-dipalmitoyl-sn-glycero-3-phosphoglycerol,sodium salt (DPPG-Na), phosphaticid acid derivatives [l,2-distearoyl-sn-glycero-3-phosphaticid acid, sodium salt (DSPA), phosphatidylethanolamine derivatives [e.g. dioleoyl-J-R-phosphatidylethanolamine (DOPE), l,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE),2-diphytanoyl-sn- glycero-3- phosphoethanolamine (DPhyPE)], JV-[l-(2,3-dioleoyloxy)propyl]-N,N,N- trimethylammonium (DOTAP), l,3-di-oleoyloxy-2-(6-carboxy-spermyl)-propylamid (DOSPER), (1,2- dimyristyolxypropyl-3-dimethylhydroxy ethyl ammonium (DMRIE), (Nl- cholesteryloxycarbonyl-3,7-diazanonane-l,9-diamine (CD AN), dimethyldioctadecylammonium bromide (DDAB), l-palmitoyl-2-oleoyl-sn-glycerol-3- phosphocholine (POPC), (b-L-Arginyl- 2,3-L-diaminopropionic acid-N-palmityl-N-olelyl- amide trihydrochloride (AtuFECTOl), N,N- dimethyl-3-aminopropane derivatives [e.g. l,2-distearoyloxy-N,N-dimethyl-3-aminopropane (DSDMA), l,2-dioleyloxy-N,N- dimethyl-3-aminopropane (DoDMA), l,2-dilinoleyloxy-N,N-3- dimethylaminopropane (DLinDMA), 2,2-dilinoleyl-4-dimethylaminomethyl [l,3]-dioxolane (DLin-K-DMA), phosphatidylserine derivatives [l,2-dioleyl-sn-glycero-3-phospho-L-serine, sodium salt (DOPS)], cholesterol}, synthetic amphiphils (SAINT- 18), lipofectin, proteins (e.g. albumin, gelatins, atellocollagen), peptides (e.g. PepFects, NickFects, polyarginine, polylysine, CADY, MPG)" combinations thereof. Lipofectin represents an example of a liposomal transfection agent. It consists of at least two lipid components, a cationic lipid N-[l-(2,3- dioleoyloxy)propyl]-N,N,N- trimethylammonium chloride (DOTMA) (DOTAP which is the methylsulfate salt) and a neutral lipid dioleoylphosphatidylethanolamine (DOPE). The neutral component mediates the intracellular release. In addition to these nanoparticle materials, the cationic peptide protamine offers an alternative approach to formulate oligonucleotides as colloids. This colloidal nanoparticle system can form so called proticles, which can be prepared by a simple self-assembly process to package and mediate intracellular release of a compound as defined herein. The skilled person may select and adapt any of the above or other commercially available or not commercially available alternative excipients and delivery systems.

In this document and in its claims, the verb "to comprise" and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus usually means "at least one".

The word "about" or "approximately" when used in association with a numerical value (e.g. about 10) preferably means that the value may be the given value (e.g. of 10) more or less 0.1% of the value. All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.

The present invention is further illustrated by the oligonucleotides mentioned in Table 1. These ONs merely serve as examples and should not be construed as limiting the scope of the invention.

Unless stated otherwise, the practice of the invention will employ standard conventional methods of molecular biology, microbiology and/or biochemistry. Such techniques are described in Green & Sambrook (2012) Molecular Cloning: A Laboratory Manual (4th edition), Cold Spring Harbor Laboratory Press; in Ausubel et al. (2004) Current Protocols in Molecular Biology, John Wiley & Sons; and in Volumes I and II of Brown (1998) Molecular Biology LabFax, Second Edition, Academic Press (UK); Oligonucleotide Synthesis: Methods and Applications (ed. Herdewijn, 2010); Nucleic Acid Hybridization (Hames and Higgins, eds.).

TABLE 1

Drug Name Company Technologies Reference Further details

defibrotide Gentium SpA Intravenous; WO00178761 single-stranded deoxyribonucleotide

Jazz Oligonucleotide defibrotide (Defitelio), for the potential iv

Pharmaceutic treatment and prevention of veno-occlusive als disease, multiple myeloma. (MM) and the

prevention of graft versus host disease

(GVHD)

mipomersen Isis Oligonucleotide WO0301 1887 antisense oligonucleotide inhibitor of

Pharmaceutic an ti sense; apolipoprotein B100 mRNA (apoB-100). The als / Genzyme Subcutaneous WO09627606 product is indicated in the US as an adjunct to lipid-lowering medications and diet, to reduce low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (TC) and non-high-density lipoprotein -c peqaptanib NeXstar Injectable; WO09818480 angiogenesis-inhibiting anti-VEGF165 aptamer

(Macugeii; Pharmaceutic Oligonucleotide; which is delivered by intravitreal injection. The Macuverse) als / Eyetech Ophthalmic; product is indicated for the treatment of

(Valeant PEGylated; neovascular (wet) age-related macular

Pharmaceutic Parenteral degeneration (AMD)

als

International)

Pfizer

fomivirsen Isis Oligonucleotide WO08807544 antisense inhibitor of cytomegalovirus (CMV)

(Vitravene) Pharmaceutic anti sense; replication, for the treatment of CMV retinitis als Parenteral; WO09203456 in AIDS patients

Systemic

drisapersen Leiden Oligonucleotide WO00224906 sc of an antisense oligonucleotide-based

(PRO-051 ; University antisense; therapeutic (2-O-metliyl antisense RNA

2402968; GSK- Medical Subcutaneous oligonucleotide) to skip exon 5 1 of the

2402968) Center dystrophin gene for the potential treatment of

Prosensa Duchenne muscular dystrophy (DMD).

(BioMarin)

revusiran (SAR- Alnylam Oligonucleotide WO20090738 siRNA therapy targeting the transthyretin

438714; ALN- Pharmaceutic conjugated; 09 (TTR) gene, delivered using a GalNAc- TTRsc) als Genzyme Subcutaneous conjugate delivery approach and subcutaneous administration for the potential treatment of TTR-mediated familial amyloidotic

cardiomyopathy (FAC)

ISIS-TTRRx Isis Oligonucleotide antisense drug that inhibits transthyretin (TTR)

(ISIS-GSKl Rx, Pharmaceutic antisense; for the potential subcutaneous treatment of

ISIS-420915) als Subcutaneous TTR amyloidosis, including familial amyloid

GlaxoSmithKl polyneuropathy (FAP) and familial amyloid ine cardi omyopathy (FAC) patisiran (ALN- Alnylarn Infusion; WO20100482 second-generation si RNA therapy using the TTR02; GZ- Pharmaceutic Intravenous; 28 MC3 lipid that targets the transthyretin (TTR)

438027) als Genzyme Nanoparticle gene delivered using Tekmira's lipid

injectable; nanoparticle technology, for the potential Oligonucleotide treatment of TTR amyloidosis

nusiners (ISIS- Genz me Intrathecal; WO20121781 antisense oligonucleotides which redirect SMNRx, ISIS- Corp Biogen Oligonucleotide 46 endogenous spli ing of the survival motor 396443. antisense neuron (SMN) 2 gene to produce functional S NRxlen SMN protein, for the potential intrathecal treatment of spinal muscular atrophy (SMA) in children and infants

ISIS-APOCIIIRx Isis Glycoprotein; WO20121494 79 amino acid glycoprotein and antisense

(ISIS-304801 ) Pharmaceutic Oligonucleotide 95 oligonucleotide that inhibit apo lipoprotein C- als / Akcea antisense; III (apoC-III) mRNA, for the potential sc Therapeutics Subcutaneous treatment of atherosclerosis and

hypertriglyceridemia associated with cardiovascular disease, type 2 diabetes and familial chylomicronemia syndrome (FCS) aqanirsen (GS- Gene Signal Emulsion; WO02103014 aganirsen (GS-101), an insulin receptor 101 ) SAS Oligonucleotide substrate- 1 (IRS- 1 ) inhibiting antisense

antisense; oligonucleotide, as an angiogenesis inhibitor, Ophthalmic; for the potential treatment of corneal graft rejection (CGR), neovascular glaucoma (NVG), retinopathy of prematurity (ROP), diabetic retinopathy, age-related macular degeneration (AMD), diabetic macular edema and ischemic central retinal vein occlusion (iCRVO)

eteplirsen (A VI- Sarepta Infusion; WO20060000 antisense-based exon-skipping pre-RNA

4658 Therapeutics Intramuscular; 57 interference technology (ESPRIT), targeted to

(formerly AVI Intravenous; skip dystrophin gene exon 51 , for the potential BioPharrna) Oligonucleotide im and iv treatment of Duchenne muscular antisense; RNA dystrophy (DMD)

technology

peqpleranib Archemix Oligonucleotide; WO20040477 PEGylated aptamer directed against PDGF-B sodium (Fovista, Corp Ophthalmic; 42 administered via intravitreal injection, for the E- 10030) Ophthotech PEGylated potential treatment of neovascular age-related macular degeneration (AMD) or wet AMD, both as a single agent and in combination with pegaptanib

iv peqnivacoqin Archemix Drug WO00226932 regimen comprising pegnivacogin (RB-006), + iv Corp Regado combination; an RNA aptamer that directly inhibits Factor anivamersen Biosciences Intravenous; IXa, and its oligonucleotide antidote (ACS-PCI), Oligonucleotide; anivamersen (RB-007), both given as iv bolus,

(Revolixys Kit) PEGylated for the potential treatment of thrombosis, particularly in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (ACS-PCI) and coronary artery bypass grafts (CABG)

DIMS-0150 Karoiinska Oligonucleotide WO09747325 antisense NF-kappaB p65 oligonucleotide that

(Kappaproct) Institutet an tisense ; Rectal ; targets TLR-9 for the potential treatment of InDex Rectal local ulcerative colitis (UC)

Pharmaceutic

als

S-4141 14 AnGes MG Dermatological; WO03091432 20-mer double-stranded DNA NFkappaB

Shionogi & Oligonucleotide decoy oligonucleotides, created using Co MEDRx's transdermal technology, for the potential dermatological treatment of atopic dermatitis

custirsen (OGX- Isis Infusion; WO00222635 clusterin mRNA-inhibiting antisense 01 1 ; ISIS- Pharmaceutic Intravenous; oligonucleotide, as a potential treatment to 1 12989; TV- als Oligonucleotide increase sensitivity of resistant solid tumors to 101 1) OncoGenex an ti sense conventional cancer therapeutics alicaforsen Isis Oligonucleotide WO09405333 antisense inhibitor of intercellular adhesion

Pharmaceutic an ti sense; Rectal; molecule (ICAM)-l mRNA, in an enema , for als Rectal local the potenticil treatment of ulcerative colitis

Atlantic (UC; as AP- 1431 ) and pouchitis (as AP-1007)

Healthcare

TKM-Ebola- Tekmira Liposome; WO201 10200 small interfering RNA (siRNA) therapeutic Guinea Pharmaceutic Nanoparticle; 23 that targets the Guinea variant of Ebola virus, als Corp Oligonucleotide; developed using Tekmira's Lipid Nanoparticle

Parenteral technology, for the potential treatment of Ebola virus infection

miR-15/16 EnGeneIC Pty Antibody; microRNA-15/16 mimics packaged in mimics Ltd Infusion; company's EDV nanocells or minicells

Intravenous; targeted with EGFR-specific antibodies

Nanoparticle including, TargomiRs (miR-16 packaged in injectable; nanocells), for the potential treatment of

Oligonucleotide recurrent malignant pleural mesothelioma

(MPM)

ALN-CC5 Alnylam Oligonucleotide; WO20141601 RNAi therapeutic targeting complement

Pharmaceutic Oligonucleotide 29 component C5 mRNA, created using GalNAc- als conjugated; siRNA conjugate technology for the potential

Subcutaneous sc treatnient of complement mediated diseases including paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, neuromyelitis optica, and membranous nephropathy

ND-L02-S0201 Nitto Denko Nanoparticle; WO20060682 Vitamin A-coupled lipid nanoparticle

Corp Oligonucleotide 32 containing si RNA against HSP47, for the potential iv treatment of fibrosis, including liver fibrosis

RG-101 (RG- Regulus Oligonucleotide WO20051078 GalNAc-conjugated microRNA antagonist, 101 RX ) Therapeutics antisense; 16 from a. program of antisense oligonucleotides

Subcutaneous which inhibit mi R- 122, for the potential treatment of HCV infection

SRP-4053 Sarepta Oligonucleotide WO20141007 follow-on compound of eteplirsen and a

Therapeutics antisense; 14 phosphorodiamidate moip olino oligomer

Parenteral; RNA (PMO) -based RNA therapeutic, targeted to technology skip dystrophin gene exon 53, for the potential treatment of Duchenne muscular dystrophy (DMD)

ISIS-AR-2.5RX Isis Infusion; WO20140592 antisense oligonucleotide that inhibits the

(ISIS-ARRx; Pharmaceutic Intravenous; 38 production of the androgen receptor (AR), for AZD-5312, ISIS- als Oligonucleotide the potential iv treatment of prostate cancer AZ IRx, LSIS- antisense and other solid tumors such as breast, bladder 560131 ) and ovarian cancers DCR-M171 1 Dicema. Infusion; WO20140433 anti-Myc Dicer-substrate si RNA (DsiRNAs),

(DCR-MYC) Pharmaceutic Intravenous; 1 1 formulated in EnCore lipid nanopaiticles, using als Nauoparticle Dicerna's Dicer Substrate Technology, for the injectable; potential injectable treatment of cancer

Oligonucleotide including hepatocellular carcinoma. (HCC), colorectal cancer (CRC), multiple myeloma, lymphoma and other solid tumors

ISIS-DMPK- Isis Oligonucleotide antisense drug that targets the DM myotonica- 2.5Rx Pharmaceutic antisense; protein kinase (DMPK) gene, for the potential als Subcutaneous; sc treatment of myotonic dystrophy type 1

Systemic (DM1, Steinert disease)

AYX-1 Adynxx Intrathecal; WO20081413 dsDNA decoy that inhibits binding of the

Oligonucleotide 08 EGR-1 transcription factor, for the potential intrathecal treatment of post-surgical pain and for the prevention of chronic pain

ARC-520 .Arrowhead Intravenous; WO20130035 N-acetylglucosamine polymer and cholesterol-

Research Oligonucleotide 20 siRNAs (chol-siRNAs) that targets the Corp antisense conserved regions of HBV transcripts and the lead from RNAi therapeutics, developed using its dynamic polyconjugates (DPC) technology, for the potential iv treatment of HBV infection

SB-01 1 sterna Dermato logical; WO201 10982 dermal of hgd40, a GATA-3 transcription biologicals Oligonucleotide 85 DNAzyme antisense oligonucleotide, for the

GmbH and Co antisense potential treatment of atopic dermatitis KG

ISIS-APO(a)Rx, Isis Oligonucleotide WO20131774 an antisense oligonucleotide that targets

( ISIS-494372: Pharmaceutic antisense; 68 apo lipoprotein A for the potential treatment of

ISIS-APOARx als / Akcea Parenteral atherosclerosis

siG12D LODER Silenseed Ltd Oligonucleotide; EP-02591770 siRNA targeting Gl 2D mutant KRAS

Systemic encompassed within a biodegradable polymeric matrix, siG12D LODER, generated using the company's Local Drug EluteR (LODER) technology, for the potential treatment of pancreatic cancer

ISIS-PTP-1 BRx Isis Oligonucleotide an antisense inhibitor of protein tyrosine

(ISIS-404173) Pharmaceutic antisense; phosphatase- I B (PTP-1 B) niRNA, for the als Subcutaneous potential treatment of type 2 diabetes

ISIS-STAT3- Isis Infusion; WO20121357 antisense oligonucleotide that inhibits STAT-3 2.5Rx Pharmaceutic Intravenous; 36 mRNA, for the potential iv infusion treatment

(ISIS-STAT3Rx; als Oligonucleotide of cancer, including NSCLC, pancreatic ductal

ISIS-481464; antisense adenocarcinoma (PDAC), colorectal cancer AZD-9150) (CRC), hematological malignancies and hepatocellular carcinoma

RXI-109 Galena Intradermal; WO201 1 1 198 self-delivering rxRNA (sd-rxRNA)

Biopharma Oligonucleotide 87 lipophi lically-enriched RNA-antisense hybrid

RXi antisense; RNA therapeutic that reduces connective tissue

Pharmaceutic antisense growth factor (CTGF) expression, for potential als use in the prevention of scar tissue formation and treatment of fibrosis and proliferative vitreoretinopathy

SB-010 Philipps- Aerosol inhalant; WO20050333 inhaled GATA-3 transcription DNAzyme

Universitat Controlled 14 hgd40 antisense oligonucleotide for the

Marburg release; potential treatment of Th2-driven asthma and

Sterna Oligonucleotide exacerbation of COPD (eCOPD) biologicals antisense

B N-053 (PRO- Prosensa. Oligonucleotide WO20090547 antisense oligonucleotide -based therapy

Therapeutics antisense; designed to skip exon 53 of the dystrophin 053) BV Parenteral 25 gene

B N-045 (PRO- Prosensa. Oligonucleotide WO20090547 antisense oligonucleotide -based therapy

045) Therapeutics antisense; 25 designed to skip exon 45 of the dystrophin

BV Subcutaneous gene, created using exon-skipping technology acquired when the company was spun out from Leiden University Medical Center (LUMC)

BMN-044(PRO- Leiden Intravenous; WO20091396 oligonucleotide -based therapy designed to skip

044) University Oligonucleotide 30 exon 44 of the dystrophin gene, created using

Medical antisense; exon-skipping technology acquired when the

Center Subcutaneous company was spun out from Leiden University

Prosensa Medical Center (LUMC)

ISIS-FXIRx Isis Oligonucleotide WO20130707 antithrombotic antisense oligonucleotide that

(ISIS -416858) Pharmaceutic antisense; 71 inhibits the production of factor XI, for the als Subcutaneous potential sc treatment of blood clotting

disorders

lexaptepid NOXXON Intravenous; WO20120555 PEGylated spiegelnier targeted to hepcidin, for peqol (NOX- Pharma AG PEGylated; 73 the potential iv or sc treatment of anemia

H.94) Spiegelnier associated with inflammation

SYL-040012 Sylentis Sau Oligonucleotide; WO20060218 siRNA targeting adrenergic receptor-be ta2

(bamosiran) Ophthalmic; 17 (ADRB2) mRNA, for the potential eye drop

Ophthalmic liquid treatment of ocular hypertension, a risk factor for primary open-angle glaucoma (PO AG)

DV-1 179 Dynavax Oligonucleotide; WO20060287 toll-like receptor (TLR.) 7 and 9 inhibitor, and

Technologies Parenteral; 42 the lead from a series of oligonucleotide, Corp Systemic endosomal TLR inhibitors, for the potential treatment of autoimmune and inflammatory diseases, including systemic lupus erythematosus (SLE) and cutaneous lupus, psoriasis, and rheumatoid arthritis (RA)

GED-0301 Giuliani SpA Oligonucleotide WO20100548 antisense oligonucleotide targeted against

(mongersen) Celgene antisense; Oral; 26 SMAD-7, a protein that blocks TGF-beta-i signaling, for the potential oral treatment of Crohn's disease

BP-100-1.01 MD Anderson Infusion; WO09801547 liposomal Grb-2; L-Grb-2 - antisense drug that

Cancer Center Intravenous; targets the adaptor protein Grb-2, for the Bio-Path Liposome; potential iv treatment of cancer, including

Oligonucleotide chronic myelogenous leukemia (CML), colon antisense; cancer and breast cancer, acute myelogenous

Systemic leukemia. (AML), acute lymphoblastic

leukemia. (ALL) and myel odysplastic syndrome (MDS)

SYL-1001. SYL- Sylentis Sau Oligonucleotide; WO20070459 TRPV1 siRNAs for the potential topical

045001 and SYL- Ophthalmic; 30 treatment of ocular pain associated with dry 045003 Ophthalmic liquid eye.

(presumed to be

SYL-054003

QPI-1007 Quark Oligonucleotide; WO20050720 modified siRNA against caspase-2, for the

(siCASP2) Pharmaceutic Ophthalmic 57 potential intravitreal treatment of ocular injury als and non-arteritic ischemic optic neuropathy

(NAION) and glaucoma

SNS-01 -T (SNS- Sevion Drag WO20070708 combination therapy of Factor 5A (eIF-5Al) 101, SNS-01 ) Therapeutics combination; 24 siRNA (NF -kappa B activation inhibitor) and a

Infusion; plasmid of the Factor 5 A gene encapsulated in

Intravenous; a nanoparticle (B29 promoter, apoptosis

Nanoparticle ^■inducer), for the potential iv infusion treatment injectable; of multiple myeloma (MM), mantle cell

Oligonucleotide; lymphoma. (MCL) and diffuse large B-cell Protein lymphoma. (DLBCL)

recombinant

CEQ-508 Cequent Oligonucleotide; WO20060660 TransKingdom RNA interference (tkRNAi)

Pharmaceutic Oral; Oral 48 therapeutic, that targets against beta-cateni , als / Marina. suspension; RNA for the potential oral prevention of familial Biotech technology adenomatous polyposis

TKM-PLK1 Protiva Infusion; WO20090828 short interfering RNAs (siRNAs) that silences

(TKM-080301 ; Biotherapeuti Intravenous; 17 the gene for polo-like kinase 1 (PLK-1) using

PLK.1 SNALP; cs / Tekmira Liposome; the company's lipid nanoparticle (LNP) PL 1 LNP) Pharmaceutic Nanoparticle delivery technology, for the potential iv

als injectable; treatment of solid tumors.

Oligonucleotide

STNM-01 Stelic Institute Oligonucleotide; WO20080204 antifibrotic si RNA agent against CHST 15,

& Co Transmucosal 89 delivered locally into the intestinal for the potential treatment of intestinal stenosis in Crohn's disease and ulcerative colitis

EXC-001 (PF- Isis Intradermal; WO20100278 2-O-methoxyethyl (2-MOE) modified

06473871) Pharmaceutic Oligonucleotide 30 antisense oligonucleotide agents that inhibit als antisense connective tissue growth factor (CTGF)

Pfizer mRNA, for the potential intradermal treatment of scarring

aqanirsen (GS- Gene Signal Dermatological; WO02103014 insulin receptor substrate- 1 (IRS- 1) inhibiting

101) SAS Oligonucleotide antisense PS oligonucleotide, as a. potential antisense angiogenesis modulator for the potential treatment of psoriasis

asvasiran University of Aerosol inhalant; WO20060625 aerosolized inhalant of asvasiran sodium sodium (inhaled South Inhalant; 96; (ALN-RSV01), an si RNA which targets the ) Alabama Oligonucleotide WO20060743 respiratory syncytial virus (RSV) N gene and

Ainylam/Kyo 46 inhibits viral replication, for the potential wa Hakko treatment or prevention of RSV infection

Kirin

miravirsen Roche Infusion; WO20071 127 locked nucleic acid (LNAs) ribonucleotides

Innovation Intravenous; 53 interspaced throughout a. DNA

Center Oligonucleotide ph osphorothi oate sequence complementary to

Copenhagen antisense; mature miR-122, a liver-specific micro RNA

A/S Subcutaneous (miRNA), for the potential treatment of HCV infection

olaptesed peqol NOXXON Intravenous; WO20090190 PEGylated spiegelmer inhibitor of stromal cell- (NOX-A12) Pharma AG Oligonucleotide; 07 derived factor-! (SDF-1 ; CXCL12), for the

PEGylated; potential iv or sc mobilization of autologous Spiegelmer; hematopoietic stem cells following

Subcutaneous transplantation in non-Hodgkin's lymphoma

(NHL), multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) patients

Nexaqon CoDa Dermatological; WO00044409 a ti-connexin 43 oligonucleotide, for the

COD A -001 , Therapeutics Oligonucleotide potential topical treatment of venous leg ulcer,

(NZ) antisense; diabetic foot ulcer and ocular wound healing

Ophthalmic

PNT-2258 ProNAi DNA technology; WO03070735 DNA interference (DNAi) therapy against Bcl-

Therapeutics Infusion; 2 oncogene, for the potential iv infusion

Intravenous; treatment of cancer including non-hodgkin's

Liposome lymphoma (NHL), prostate cancer, melanoma mjectable; and breast cancer and other Bcl-2 -driven

Oligonucleotide tumors

IMO-3100 Idera Oligonucleotide; WO20070473 DNA -based antagonists of TLR-9 and TLR-7,

Pharmaceutic Subcutaneous 96 for the potential sc treatment of autoimmime als diseases, and inflammatory diseases, including lupus, rheumatoid arthritis, multiple sclerosis, psoriasis, colitis and HIV-infection

ISIS-GCCR-Rx Isis Intraveno s; WO20130633 antisense oligonucleotide targeting the

Pharmaceutic Oligonucleotide 13 glucocorticoid receptor, for the potential sc als antisense; treatment of type 2 diabetes and Cushing's

Subcutaneous Syndrome

ISIS-GCGRRx Isis Infusion; WO20080170 generation 2.2 antisense oligonucleotide, which

Pharmaceutic Intravenous; 81 inhibits glucagon receptor (GCGR) mRNA, for a!s Oligonucleotide the potential sc injection or iv infusion

antisense; treatment of type 2 diabetes

Subcutaneous

Atu-027 Silence Infusion; WO20040199 siRNA that suppresses protein kinase N3

Therapeutics Intravenous; 73 (PKN3) expression for the potential iv

AG Liposome treatment of solid tumors, primarily pancreatic injectable; cancer

Oligonucleotide

emapticap NOXXON Intravenous; WO20070934 PEGylated, high affinity L-RNA peqol (NOX- Pharma AG Oligonucleotide; 09 oligonucleotide (Spiegelmer) that inhibits

E36) PEGylated; monocyte chemoattractant protein- 1 (MCP-1 ;

Subcutaneous CCL2), for the potential iv or sc treatment of complications arising from type 2 diabetes, including diabetic nephropathy

QPI-1002 Quark Intravenous; WO20060354 ^■injectable synthetic siRNA therapy that

(DGFi; PFTi; Pharmaceutic Oligonucleotide 34 temporarily and reversibly inhibits p53 for the AKIi-5; I-5NP; als potential use during surgery for preventing 15NP) acute kidney injury (AKI), and for the potential prevention of delayed graft ^'function (DGF) in kidney transplantation patients

PF-04523655 Quark Injectable; WO00012139 modified 19-nier siRNA therapy designed to (RTP-801i-14; Pharmaceutic Oligonucleotide; inhibit hypoxia-inducible gene RTP801 RTP-80H; als Ophthalmic; (DDIT4 for the potential treatment of age- REDD-14-NP, related macular degeneration (AMD) and

PF-4523655, PF- diabetic macular edema. (DME)

655; I'M ·

4523655)

apatorsen University of Infusion; WO20040306 heat shock protein 27 (lisp 27) mRNA sodium (OGX- British Intravenous; 60 inhibitors which disrupts androgen receptor 427) Columbia Intravesical; function and enhances its degradation, for the

OncoGenex Oligonucleotide potential once-weekly injectable treatment of

Pharmaceutic antisense cancer

als

REP-9AC REPLICor Infusion; WO20061224 phosphorothioate oligonucleotide (PS-ODN),

Intravenous; 09 developed using the company's DNA-based

Oligonucleotide aniphipathic polynier technology (nucleic acid- based polymer (NAP)), for the potential treatment of HBV and hepatitis D virus infection and of other viral infections, including influenza, CMV and RSV asvasiran University of Nasal systemic; WO20060625 siRNA that targets the respiratory syncytial sodium South Oligonucleotide 96; virus (RSV) N gene and inhibits viral

Alabama WO20060743 replication, for the potential treatment or Ainylam / 46 prevention of RSV infection Kyowa Hakko

Kirin

ATL-1 103 Anti sense Oligonucleotide WO20040789 antisense oligonucleotide designed to inhibit

Therapeutics antisense; 22 IGF-1 mRNA and block growth hormone

Ltd Subcutaneous receptor expression, for the potential sc treatment of disorders associated with

excessive growth hormone action including acromegaly, and diabetic retinopathy, diabetic nephropathy and for the potential treatment and prevention of certain cancers

RX-0201 Rexahii Intravenous; WO20040162 antisense oligonucleotide inhibitor of AKT1

(Archexin) Pharmaceutic Oligonucleotide 15 protein kinase expression, for the potential iv als anti sense treatment of solid tumors including renal cell carcinoma (RCC), pancreatic and ovarian cancer

ACT-GRO-777 Aptamera Infusion; WO00061597 antisense oligonucleotide aptamer that binds to

(formerly AS- Advanced Intravenous; nucleolin to reduce Be 1-2 expression, for the 141 1 ; AGRO- Cancer Oligonucleotide potential iv infusion treatment of acute myeloid 100; GRO-26B) Therapeutics antisense leukemia (AML)

(ACT

AS -8 (TPI- TOPIGEN Drug WO09966037 inhaled combination of two RNA-targeting ASM-8) Pharmaceutic combination; antisense oligonucleotides, TOP-004 (a 19- als Inhalant; WO20060452 mer), which is targeted to the beta-subunit of

(Pharmaxis) Oligonucleotide 02 IL-3, IL-5 and GM-CSF receptors, and TOP- antisense 005 (a. 21-mer), which is targeted to CCR3, for the potential treatment of asthma litenimod (Li-28) Oligovax SAS Oligonucleotide; an immunomodulatory 26mer

Parenteral phosphorothioate DNA oligonucleotide (PS) containing CpG, for the potential treatment of cancer

BL-7040 Hebrew Oligonucleotide WO03002739 oligonucleotide polymer and an oral activator

(formerly EN- University of antisense; Oral of the anti -inflammatory immune protein TLR- 101 ; Monarsen) Jerusalem 9, for the potential treatment of inflammatory

BioLineRx bowel disease (IBD) including ulcerative colitis (UC), and other inflammatory and autoimmune diseases

trabedersen Isama Intratumoral; WO09425588 phosphorothioate TGF beta. 2-specific

(AP- 12009, Therapeutics Intravenous; antisense oligodeoxynucleotide, for the presumed to be GmbH Oligonucleotide potential intravenous treatment of solid tumors AP-2/09) antisense overexpressing TGF beta 2, including

colorectal, pancreatic cancer and melanoma

ATL-1 102 Is is Oligonucleotide WO00020635 Antisense Therapeutics (ANP), under license (formerly TV- Pharmaceutic antisense; from Isis Pharmaceuticals, is developing ATL- 1 102: ISIS- als Subcutaneous 1 102, a second-generation antisense nucleotide 107248) inhibiting CD49d (a subunit of VLA-4) mRNA, for the potential sc treatment of multiple sclerosis

IMO-2055 Idera Oligonucleotide; WO00183503 immunomodulatory oligonucleotide (IMO) (IMOxine, HYB- Pharmaceutic Subcutaneous toll-like receptor 9 agonist, for the potential sc 2055, EMD- als combination treatment of cancer

1201081 )

OHR-118(AVR- Advanced Oligonucleotide US06312602; Immunomodulatory and anti -inflammatory

1 18, Reticulose, Viral conjugated; WO02056833 peptide nucleic acid (PNA) preparation, for the Product R, Research Peptide; potential treatment of cachexia, the symptoms substance R) Corp Ohr Subcutaneous of cancer and rheumatoid arthritis (RA)

Pharmaceutic

al

imetelstat Geron Corp Infusion; WO20050239 lipid-conjugated 13-mer thiophosphoramidate

(GRN- 163L, Intravenous; 94 oligonucleotide and the lead in a series of NSC-754228, Lipid; telomerase inhibitors, for the potential iv IND-1 10934; Oligonucleotide treatment of various cancers, including breast formerly GRN- antisense; cancer, non-small -cell lung cancer (NSCLC), 719) Oligonucleotide multiple myeloma (MM), myelofibrosis (MF), conjugated niyelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)

ARC-AAT Arrowhead Intravenous; unlocked nucleobase analog (UNA)-containing

Research Oligonucleotide siRNA agent that targets the mutant Z-allele in

Corp alpha- 1 -antitrypsin (AAT) deficiency,

incorporating its Dynamic PolyConjugate (DPC) technology and Arcturus' UNA chemistry, for the potential treatment of liver disease associated with AAT deficiency (AATD)

ALN-PCSsc Alnylam Nanoparticle siRNAs that silence the gene for proprotein

Pharmaceutic injectable; convertase subtilisin/kexin type 9 (PCSK9), als Oligonucleotide; formulated using MC3 lipid nanoparticles and

Protein delivered using proprietary Enhanced conjugated; Stabilization Chemistry(ESC)-GalNAc-

Subcutaneous siRNA conjugate platform, for the potential sc treatment of hypercholesterolemia

Nek2 siRNA Nagoya Intra tumoral; siRNA therapy, for the potential treatment of therapy University Oligonucleotide cancer including cholangiocarcinoma and pancreatic cancer

ISIS- Isis Oligonucleotide antisense oligonucleotide that targets

ANGPTL3RX Pharmaceutic antisense; angiopoietin-like 3 protein (ANGPTL3), for als (Akcea. Parenteral the potential treatment of hyperlipidemia Therapeutics)

ISIS-PKKRx Isis Oligonucleotide WO20150316 antisense oligonucleotide that inhibits the

Pharmaceutic antisense; 79 production of prekallikrein (PKK), for the als Systemic potential once-weekly prevention of hereditary angi oedema

ALN-AT3 Alnylam Oligonucleotide; WO20131634 siRNA oligonucleotide against an ti thrombin

Pharmaceutic Subcutaneous 30 mRNA, using the company's proprietary als Enhanced Stabilization Chemistry (ESC)-

OalNAc-siRNA conjugate deliveiy technology, for the potential once-weekly, once -monthly or twice-monthly sc treatment of hemophilia. (A and B) and rare bleeding disorders

TKM-HBV Tekmira Intravenous; unlocked nucleobase analog (UNA)-containing

(TKM-HepB) Pharmaceutic Liposome; short interfering RNA (siRNA) which targets als Corp Nanoparticle multiple sites on the HBV genome and

injectable; eliminates surface antigen expression,

Oligonucleotide including TKM-HBV 1 and TKM-HBV2, delivered using Tekmira' s lipid nanoparticle (LNP) technology and Arcturus' UNA chemistry, for the potential iv treatment of hepatitis B virus infection

MRX-34 (MRX- Mima Intravenous; WO20061379 tumor suppressor microRNA mimics, miR-34 01 ; MiR-Rx34; Therapeutics Liposome; 41 developed using Marina Biotech miR-34 mimetic) Oligonucleotide SMARTICLES liposomal nanoparticle

deliveiy technology under license from Marina. Biotech, for the potential iv treatment of cancer including liver cancer

TDM-812 3-D Matrix Intratumoral; siRNA drug that inhibits the R.PN2 (doiichyl- Ltd Oligonucleotide diphosphooligosaccharide-protein

glycosyl transferase subunit 2) gene using an A6K peptide carrier, for the potential intratumoral treatment of breast cancer including triple -negative breast cancer siRNA Quark Oligonucleotide; siRNA therapeutics, using molecular-targeted therapeutics Pharmaceutic Parenteral lipid nanoparticle drug delivery system, for the

(fibrosis), als potential treatment of fibrosis

Quark/Nitto Nitto Denko

Denko

BAX-499 (ARC- Archemix Oligonucleotide; WO201 10224 inhibitor of tissue factor pathway inhibitor 19499) Corp Baxter Subcutaneous 27 (TFPI) and subcutaneously-administered

aptamer, for the potential treatment of hemophilia. A and B

sc depot Archemix Drug WO20121491 REG-2, a regimen comprising sc depot- peqnivacoqin + Corp Regado combination; 98 administered pegylated-aptamer Factor IXa iv bolus Biosciences Intravenous; antagonist pegnivacogin (RB-006) and its anivamersen Oligonucleotide;; oligonucleotide antidote anivamersen (RB-007; (DVT), Reqado Subcutaneous; delivered separately as an iv bolus), for the

Sustained release potential treatment of deep vein thrombosis

EZN-4176 Roche Infusion; WO20090680 androgen receptor (AR) mRNA antagonist,

Innovation Intravenous; 33 locked-nucleic antisense oligonucleotides

Center Oligonucleotide WO20120650 (LNA-ON), for the potential iv infusion

Copenhagen anti sense 51 treatment of castration-resistant prostate cancer

A/S (CRPC)

ISIS-FGFR4RX University of Oligonucleotide WO20040031 FGF4 receptor targeted antisense

Queensland anti sense; 79 oligonucleotides, for the potential treatment of

Parenteral; WO20090461 obesity

Systemic 41

ALN-TTR01 Alnylam Infusion; WO20100175 siRNA therapy targeting the transthyretin

Pharmaceutic Intravenous; 09 (TTR) gene delivered using Tekmira als Nanoparticle Pharmaceuticals' stable nucleic acid-lipid injectable; particles (SNALP), for the potential iv Oligonucleotide treatment of TTR amyloidosis, including

familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy and type 2 diabetes

SPC-3920 Roche Oligonucleotide WO20120680 Locked Nucleic Acid (LNA) -c ontaining

Innovation antisense; 00 antisense oligonucleotide targeting ERBB3

Center Parenteral; (HER-3) mR A, for the potential treatment of

Copenhagen Systemic cancer

A/S

SPC-5001 Roche Oligonucleotide WO20080437 Locked Nucleic Acid (LNA) antisense

Innovation antisense; 53; oligonucleotides that target PCSK9 mRNA, for

Center Parenteral; WO20081322 the potential sc treatment o f

Copenhagen Subcutaneous 34; hypercholesterolemia

A/S WO20081389

04;

WO20090275

27;

WO20090680

33;

WO20090710

82;

WO20090716

80;

WO20090716

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GNKG-168 Changchun Infusion; an immunostimulatory oligodeoxynucleotide

Huapu Intraveno s; containing deoxycytidyl deoxyguanosine

Biotechnolog Oligonucleotide dinucleo tides (CpG ODNs), for the potential iv y Co Ltd treatment of B cell chronic lymphocytic

leukemia AZD-1419 Dynavax Inhalant; WO20080736 lead from a. program of pulmonary delivered,

Technologies Oligonucleotide 61 second-generation to 11 -like receptor 9 (TLR9) Corp agonist imrmtno stimul at oiy sequences (ISS), that modify an immune response with the result of suppression of Th2 cell activation, for the potential treatment of asthma, and COPD

TD-101 TransDerm Intradermal; siRNA therapeutics that target a point mutation

Oligonucleotide in the keratin 6A gene, including TD- 101 (TD- K6a.513a.12; Reveker) and a self-delivery version of TD-101 that is chemically modified to enhance cellular uptake (presumably sdTD- K6a.5 i 3a.12), for the potential intradermal treatment of pachyonychia congenita. (PC)

TKM-Ebola Protiva Intravenous; WO201 10114 siRNA s using its LNP technology (formerly (TKM- 100201 ; Biotherapeuti Liposome; 47 stabilized nucleic acid lipid particles (SNALP) Pro-EBOV, cs Nanoparticle delivery system), as TKM-Ebola which targets

TKM- 100802) injectable; an undisclosed filovirus gene for the potential

Oligonucleotide iv treatment of Ebola

ALN-VSP (ALN- Alnylam Infusion; WO20091 1 16 a lipid-delivered composite of VEGF and VSP01 ; ALN- Pharmaceutic Intravenous; 58 kinesin spindle protein (KSP)-gene-silencing VSP02; ASC-06) als Liposome; RNAs (siRNAs), for the potential iv treatment

Nanoparticle of solid tumors, specifically liver tumor injectable;

Oligonucleotide

ALN-PCS Alnylam Infusion; WO20071341 siRNAs that silence the gene for proprotein

(ALN-PCS02; Pharmaceutic Intravenous; 61 convertase subtilisin/kexin type 9 (PCSK.9), ALN-PCSK) als Nanoparticle formulated using Tekmira's MC3 lipid

injectable; nanoparticles, for the potential iv infusion Oligonucleotide treatment of hypercholesterolemia.

SPC-4955; SPC- Roche Oligonucleotide WO20070310 apolipoprotein B-100 inhibitors which included

3197, SPC-3833 Innovation anti sense; 81 and were based upon its locked nucleic acid and SPC-4068 Center Subcutaneous (LNA) technology platform for the potential sc

Copenhagen treatment of hyperlipidemia A/S

cenersen (EL- Eleos Intravenous; WO09303770 p53 ph osphorothi oate antisense

625, Aezea) Oligonucleotide oligonucleotide, for the potential iv treatment antisense of myelodysplastic syndrome

RG-6061 Cureon A/S Infusion; WO03085110 RG-6061 (SPC-2968; aiiti-HIF-1 alpha. LNA

Intravenous; AS-ODN), a Locked Nucleic Acid (LNA) Oligonucleotide WO20060507 antisense oligonucleotide targeting hypoxia- antisense 34 inducible factor (tllF)-l alpha mRNA, for the potential injectable treatment of solid tumors

SPC-3042 Roche Injectable; WO20040699 Locked Nucleic Acid (LNA) antisense

Innovation Oligonucleotide 91 oligemic leotide-targeting survivin mRNA, for

Center antisense; the potential treatment of cancer

Copenhagen Parenteral

A/S

IGF-1 receptor Thomas Drag implant; WO00()09145 autologous tumor cell immunotherapy, using oliqodeoxvnucle Jefferson Oligonucleotide an antisense oligodeoxynucleotide of the IGF-I otide-based University antisense receptor (IGF-1 R/AS ODN), administered via immunotherapv diffusion chamber implants, for the potential treatment of glioma.

STAT3 decovs University of Oligonucleotide; STAT3 decoys, double-stranded DNA decoys (cancer), Pittsburgh Parenteral which bind to the activated STAT3 protein and prevent it from activating other cancer related genes, for the potential iv treatment of STAT 3 activated cancers NS-065 Nippon Oligonucleotide WO 12029986 morpholino based antisense oligonucleotide, Shinyaku Co antisense; targeted to skip dystrophin gene exon 53, for

Ltd Parenteral the potential treatment of Duchenne muscular dystrophy (DMD)

AMG-0102 AnGes MG Oligonucleotide; NFkappa B decoy oligonucleotides, including

Parenteral chimeric molecules that target a second

transcription factor such as E2F or Ets, for the potential treatment of vascular disorders including aneurysm and restenosis

ECP-102 Ryboquin Ltd Intravenous; apoptosis enhancer, developed using the

Nanoparticie company's proprietary LipTide siRNA injectable; nanoparticie technology which blocks the

Oligonucleotide; ubiquitin ligase and thereby increases p73

Peptide protein level, for the potential iv treatment of cancer.

ISIS-GSK6-LRX Isis Oligonucleotide antisense oligonucleotide for the potential

Pharmaceutic antisense; treatment of viral infections als Parenteral

ISIS-ANGPTL3- Isis Oligonucleotide antisense oligonucleotide that targets LRx Pharmaceutic antisense; aiigiopoietin-like 3 protein (ANGPTL3-L), for a is Parenteral the potential treatment of hyperlipidemia.

ACTX-01 Avrygen Corp Nanoparticie; nanoparticie siRNA therapy platform for the

Oligonucleotide potential treatment of glioblastoma.

miR-29 University of Oligonucleotide; micro RNA therapeutic, downregulating SSc therapeutic Zurich Parenteral fibroblasts, for the potential treatment of scleroderma

miR-155 miRagen Oligonucleotide; micro RNA therapeutic targeting miR-155, for inhibitors Therapeutics Parenteral the potential treatment of hematological malignancy and Amyotrophic lateral sclerosis (ALS)

miR-708 (breast MirCan Oligonucleotide; miR-708 for the potential prevention of breast cancer), MirCan Therapeutics Parenteral cancer including triple negative breast cancer. Therapeutics LLC

ISIS-APO(a)- Isis Oligonucleotide an antisense oligonucleotide that targets LRx Pharmaceutic antisense; apo lipoprotein A, for the potential treatment of als Parenteral cardiovascular diseases including

atherosclerosis, coronary heart disease, heart attack and stroke.

sdRNA BioAxone Oligonucleotide; small interfering RNAs (sdRNA), targeting therapeutic Biosciences Parenteral; RNA PTEN, using a. RNAi delivery technology, for technology the potential treatment of spinal cord injur}'

(SCI)

MTfp+siRNA biOasis Oligonucleotide; peptide version of melanotransferrin (MTfp) qene silencinq Technologies Protein fusion and a siRNA therapeutic, as a Transcend- proqram siRNA that allows transport across the blood- brain barrier, for the potential treatment of stroke and amyotrophic lateral sclerosis (ALS) miR-Rx16 Mima Oligonucleotide niiR-Rx 16, a miR- 16 mimic for the potential

Therapeutics treatment of cancer

miR-1291 Mirna Oligonucleotide; miR-1291 (microRNA-1291) replacement replacement Therapeutics Parenteral therapy, a tumor suppressor miRNA for the therapy potential treatment of pancreatic cancer

IL-10 Anvil Oligonucleotide IL-10 transcriptional activators developed transcriptional Biosciences using endogenous transcriptional activation activators LLC and oligonucieotide-based technology, for the (uveitis), Anvil Biosciences potential treatment of uveitis

SCN8A splicing LifeSplice Oligonucleotide; splice modulating oligonucleotides (SMOs), targeted SMOs Phamia LLC Oligonucleotide targeting SCN8A splicing, for the potential antisense; treatment of Dravet syndrome

STP-302 Simaomics Oligonucleotide; siRNA therapeutic for the potential treatment

Parenteral of colon cancer

anti-CD22 Isis Antibody anti-alpha-CD22 antibody-MXD3 antisense antibodv- XD3 Pharmaceutic conjugated; oligonucleotide conjugates for the potential antisense a Is Oligonucleotide treatment of precursor B-cell acute oliqonucleotide antisense lymphoblastic leukemia

coniuqates

Kruppel-like Isis Oligonucleotide erythroid Kruppel-like factor 1 (KLF1) factor 1 - Pharmaceutic antisense expression-targeting antisense oligonucleotides tarqetinq als (ASO) for the potential treatment of sickle cell antisense disease

oliqonucleotide

anti-anqioqenic InteRNA Oligonucleotide; miRNA-based therapeutics targeting miRNA-based Technologies Parenteral angiogenesis, for the potential treatment of therapeutics BV renal cell canecr and glioblastoma multiforme

SNA based AuraSense Oligonucleotide spherical nucleic acid (SNA) based therapeutic, therapeutic Therapeutics for the potential treatment of liver diseases

LLC

AST-008 AuraSense Oligonucleotide WO20150136 spherical nucleic acid (SNA) based therapeutic,

Therapeutics 73 as an immunotherapy, for the potential

LLC treatment bladder cancer

AST-006 AuraSense Oligonucleotide spherical nucleic acid (SNA) based therapeutic,

Therapeutics for the potential treatment of diabetic ulcer

LLC

AST-005 AuraSense Dermatological; spherical nucleic acid (SNA) based therapeutic,

Therapeutics Oligonucleotide for the potential topical treatment of psoriasis

LLC

SYN-01 tricvclo- University of Oligonucleotide tri eye 1 o(tc) -DNA based antisense

DNA antisense Bern antisense; oligonucleotides developed using its oliqonucleotides Parenteral proprietary tricyclo-DNA technology platform, for the potential treatment of Duchenne muscular dystrophy

QR-110 ProQR Oligonucleotide RNA correction therapeutic, which targets

Therapeutics CEP290 mRNA, for the potential treatment of BV Leber's Congenital Amaurosis LCA).

miR-486 Nanjing Oligonucleotide myocardial injury

Medical

University

DsiRNA-EX Dicerna. Oligonucleotide; DsiRNA-EX (extended Dicer substrate RNA) coniuqates Pharmaceutic Oligonucleotide conjugates, for the potential treatment of (liver diseases), als conjugated; undisclosed rare diseases involving the liver. Dicerna Parenteral

anti-IL-17a Zenyaku Oligonucleotide RNA aptamers targeting IL-17A, including aptamers ogyo Co Ltd 17M-340, for the potential use in the treatment (inflammatory of rheumatoid arthritis (RA).

disease),

ALN-PDL Alnylam Oligonucleotide; RNAi therapeutic targeting hepatoeyte- Pharmaceutic Subcutaneous expressed hepatocyte-expressed programmed als death ligand 1 (PD-L1), developed using

Enhanced Stabilization Chemistry (ESC)- GalNAc-conjugate technology for the potential sc treatment of chronic liver infections

ALN-HDV Alnyiam Oligonucleotide; RNAi therapeutic targeting the hepatitis delta

Pharmaceutic Subcutaneous virus (HDV) genome, developed using ais Enhanced Stabilization Chemistry (ESC)- GalNAc-conjugate technology for the potential sc treatment of chronic HDV infection.

ISIS-GSK5- Isis Oligonucleotide an antisense oligonucleotide targeting 2.5Rx Pharmaceutic antisense; rhodopsin for the potential treatment of an a!s Parenteral ocular disease including autosomal dominant retinitis pigmentosa

ISTH-0036 Isarna Oligonucleotide TGF-beta 2 antisense oligonucleotide for the

Therapeutics potential treatment of glaucoma

GmbH

allele-specific University of Oligonucleotide allele-specific, locked nucleic acid (LNA) antisense British antisense antisense oligonucleotides for the potential oliqonucleotides Columbia treatment of Huntington's disease

RBM-007 Ribomic Oligonucleotide anti-Gbroblast growth factor 2 aptamer, for the potential treatment of osteoarthritis, rheumatoid arthritis, cancer pain and age- related macular degeneration

EGLN1 siRNA Merck Nanoparticle; siRNA targeting EGLNi, the gene encoding

Research Oligonucleotide; the prolyl-4-hydrolase 2 (PHD2) protein, for

Laboratories Parenteral the potential treatment of anemia

ALNG-01 Alnylam Oligonucleotide; siRNA therapy targeting glycolate oxidase

Pharmaceutic Oligonucleotide (GO), delivered using a enhanced stabilization als conjugated; chemistry (ESC)-GaiNAc conjugate delivery

Subcutaneous approach, for the potential sc treatment of primary hyperoxaluria type 1 (PHI) oligonucleotide Competence Oligonucleotide modified antisense oligonucleotide

TrkA/TrkB Centre for tropo myo sin-related kinase (TrkA and TrkB) inhibitors Cancer receptor inhibitors for the potential treatment

Research of cancer

neuronal nLife Oligonucleotide neuronal specific oligonucleotides (nOligos), specific Therapeutics antisense; which target inflammation genes in glia for the oliqonucleotides SL Parenteral potential treatment of neuroinflammation neuronal nLife Oligonucleotide neuronal specific oligonucleotides (nOligos) specific Therapeutics antisense; for the potential treatment of duchenne oliqonucleotides SL Parenteral muscular dystrophy

nOligos nLife Oligonucleotide neuronal specific oligonucleotides (nOligos),

Therapeutics antisense; targeting amyloid precursor protein in SL Parenteral hippocampal, striatal and cortical neurons, developed using its oligonucleotide delivery platform, for the potential treatment of Alzheimer 's disease

nOligos nLife Oligonucleotide neuronal specific oligonucleotides (nOligos), (Huntingtons Therapeutics antisense; targeting huntingtin in striatal and cortical disease) SL Parenteral neurons for the potential treatment of

Huntington's disease.

ALN-AGT Alnylam Oligonucleotide; RNAi therapeutic targeting angiotensinogen

Pharmaceutic Oligonucleotide (AGT), developed using Enhanced als conjugated; Stabilization Chemistry (ESC)-GalNAc-siR A

Subcutaneous conjugate technology, for the potential sc treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia.

Dual SomaLogic Oligonucleotide WO20150353 VEGF and PDGF-B for the potential treatnient

VEGF/PDGF-B- 05 of age-related macular degeneration targeting

SOMAmers

GSO-329 and Idera Oligonucleotide gene-silencing oligonucleotides (GSOs) that GSO-495 Pharmaceutic antisense; inhibit 14q32 microRNAs (miRs), including, als Parenteral miR-329, miR-487b, miR-494 and miR-495, for the potential treatment of choroidal neovascularization

anti-tan antisense Washington Oligonucleotide tau-targeting antisense oligonuclotides (ASOs), oligonucleotides University in antisense including ASO-12, for the potential treatment

(neurodegenerati St Louis of tau-based neurodegenerative disorders ve disorders)

pGBI-161 Gradalis Oligonucleotide; triple oncogene-targeting bifunctional s RNA

RNA technology that targets SRC-3, EGFR and K.RAS, for the potential treatment of lung cancer.

M12-PMO Tianjin Oligonucleotide homing peptide (Mi 2) conjugated with

Medical conjugated; morpholino oligomers (PMOs), for the

University Peptide; Protein potential treatment of Duchenne muscular conjugated dystrophy

frataxin RaNA Oligonucleotide WO20150239 oligonucleotides that upregulate frataxin gene upregulating Therapeutics 75 for the potential treatment of Friedreich's ataxia program

(Friedreich's

ataxia.)

SMN2 RaNA Oligonucleotide spinal motor neuron 2 (SMN2) gene upregulating Therapeutics upregulating oligonucleotide for the potential program treatment of spinal muscular atrophy.

WAV-M 01 WaVe Life Oligonucleotide chirally pure nucleic acid therapeutic, for the

Sciences potential treatment of cancer

WAV-401 WaVe Life Oligonucleotide chirally pure nucleic acid therapeutic, for the

Sciences potential treatment of an undisclosed rare disease.

ONT-87 WaVe Life Oligonucleotide RNA therapeutic (RIPtide) ONT-87, as an

Sciences antisense; RNA antisense program, for the potential treatment antisense of a metabolic rare disease.

ALN-AC3 Alnylam Oligonucleotide; WO201 1 1417 RNAi therapeutic which targets apolipoprotein

Pharmaceutic Subcutaneous 03 C-III (apoCI.il), using the company's als proprietary GaiNAc-siRNA conjugate deliveiy technology, for the potential sc treatment of severe hypertriglyceridemia

paclitaxel-PCat- Optimum Oligonucleotide survivin siRNA loaded in a fusogenic lipid to siRNA survivin Therapeutics destabilize (lie endosomal membrane plus

(cancer), LLC paclitaxel to perturb the endosomal si RNA transport (paclitaxel-PCat) (paclitaxel-PCat- siRNAsurvivin), for the potential treatment of cancers, including bladder cancer antibacterial Procarta. Antibiotic; Clostridium difficile infection

compounds Biosystems Nanoparticle;

(snare/nanoparticl Ltd Oligonucleotide;

e , Clostridium

difficile

infection)

antibacterial Procarta Antibiotic; DNA-based snare antibacterial compounds, compounds Biosystems Nanoparticle; which consist of an oligonucleotide targeting (snare/topical Ltd Oligonucleotide; essential bacterial genes and a bacterial- nanoparticle , specific nanoparticle delivery system, for the

MRSA) potential topical treatment of MRSA infection ASncmtRNA Andes Oligonucleotide (ASO) therapy targeting non-coding

Biotechnologi antisense; RNA mitochondrial RNA transcripts, including es antisense ASncmtRNA, for the potential treatment of renal cell carcinoma

nicotinamide N- Isis Oligonucleotide ASO that act by inhibiting nicotinamide N- methvltransfera Pharmaceutic antisense; methyltransferase (NNMT), for the potential se antisense als Parenteral treatment of obesity and diabetes oliqonucleotides

si RNA gagomers Quiet Nanoparticle; siRNA therapy delivered using gagomers, particles (cancer) Therapeutics Oligonucleotide lipidated glycosaminoglycan particles for the potential treatment of cancer

TKM-HTG Tekmira Liposonie; siRNA therapeutics delivered by Tekmira's

Pharmaceutic Nanoparticle; lipid nanoparticle (LNP) technology, for the als Corp Oligonucleotide; potential treatment of hypertriglyceridemia.

Parenteral

Atu-112 Silence Liposome siRNA agent that targets angiopoietin-2

Therapeutics injectable; (angpt-2) formulated using the company's pic Oligonucleotide; AtuPLEX liposome (lipoplex) delivery system,

Parenteral for the potential treatment of acute lung injury

SAMiRNA Bioneer Corp Nanoparticle; Bioneer's Self-Assemb!ed-Micelle-inhibitory- program (liver Oligonucleotide; RNA (SAMiRNA) technology, for the cancer) Prodrug potential treatment of liver cancer antisense Women & Oligonucleotide antisen se pho sphorothi o-o li gonucl eo tides phosphoroTHIO Infants antisense; (PTOs) that inhibit human epididymal

Hospital of Parenteral secretory protein E4 (ITE4; WFDC2) gene for oliqonucleotides Rhode Island the potential treatment of ovarian cancer (ovarian cancer)

SRP-4008 Sarepta Oligonucleotide PMO-based antisense RNA therapeutic,

Therapeutics antisense; targeted to skip dystrophin gene exon 8, for the

Parenteral potential treatment of Duchenne muscular dystrophy (DMD)

SRP-4055 Sarepta. Oligonucleotide PMO-based antisense RNA therapeutic,

Therapeutics antisense; targeted to skip dystrophin gene exon 55, for

Parenteral the potential treatment of Duchenne muscular dystrophy (DMD)

SRP-4052 Sarepta Oligonucleotide PMO-based antisense RNA therapeutic,

Therapeutics antisense; targeted to skip dystrophin gene exon 52, for

Parenteral the potential treatment of Duchenne muscular dystrophy (DMD)

SRP-4044 Sarepta Oligonucleotide WO20141532 PMO-based antisense RNA therapeutic,

Therapeutics antisense; 20 targeted to skip dystrophin gene exon 44, for

Parenteral the potential treatment of Duchenne muscular dystrophy (DMD)

RXI-209 RXi Oligonucleotide; liver fibrosis

Pharmaceutic Parenteral

als Corp

sshRNA aqents SomaGenics Oligonucleotide short synthetic hairpin RNA agents (sshRNA), (wound antisense; for the potential treatment of wound healing healinq), Parenteral

SomaGenics

hepatitis D virus SomaGenics Oligonucleotide short synthetic hairpin RNA agents (sshRNAs), infection antisense; for the potential treatment of hepatitis D virus

Parenteral infection

sshRNA aqents SomaGenics Oligonucleotide short synthetic hairpin RNAs (sshRNAs), for (HBV infection), antisense; the potential treatment of HBV infection SomaGenics Parenteral

anti-mortalin Tel Aviv Oligonucleotide mortalin (HSPA9

siRNA agent University

EXT-500 Extend Oligonucleotide; alcoholic liver disease

Biosciences Protein

conjugated;

Subcutaneous;

LUNAR-101 and Arctunis Oligonucleotide; transthyretin (TTR)-mediated amyloidosis LUNAR- 102 Therapeutics Parenteral including TTR-mediated polyneuropathy and cardiomyopathy

EGFRAS GPNAs University of Oligonucleotide EGFR antisense agents (EGFRAS) which

Pittsburgh antisense; comprise of guanidinium peptide nucleic acids

Parenteral; (GPNA) for the potential treatment of head and Peptide neck cancer

human CDC45 Hong Kong Oligonucleotide human replication-initiation protein CDC45, tarqeted University of antisense; for the potential treatment of cancer antisense Science & Parenteral

oliqonucleotides Technology

DsiRNAs- Dicema Oligonucleotide; WO20150031 alpha 1 antitrypsin (AAT for the potential tarqetinq alpha Pharmaceutic Parenteral 13 treatment of AAT deficiency

1 antitrypsin, als

Dicerna

Pharmaceutical

s

DsiRNAs Dicema Oligonucleotide; Dicer-substrate siRNAs (DsiRNAs) that target tarqetinq Pharmaceutic Parenteral thrombin

thrombin als

(clottinq

disorder),

Dicerna

Pharmaceutical

s

DCR-PH1 Dicema Lipid; Dicer Substrate RNA (DsiRNA) molecule that

Pharmaceutic Nanoparticle; inhibits glycolate oxidase delivered using als Oligonucleotide EnCore lipid nanoparticle technology for the potential treatment of primary hyperoxaluria 1 (PHI )

HoxA 1 gene- Harvard Liposome lipid nanoparticle-formulated small interfering silencing siRNA Medical injectable; RNA (siRNA) agents, targeted to HoxA 1 gene, therapeutics School Nanoparticle for the potential treatment or prevention of injectable; cancer, including breast cancer

Oligonucleotide;

RNAi Silence Oligonucleotide lung cancer

therapeutic Therapeutics

(DACC, lunq pic

cancer), Silence

RNAi Silence Lipid; liver fibrosis.

therapeutic Therapeutics Oligonucleotide;

(DBTC, liver pic Parenteral

fibrosis),

Silence

Therapeutics

Atu-1 112 Silence Liposome siRNA that targets angiotensin-2, formulated in

Therapeutics injectable; the company's AtuPLEX liposome (lipoplex) pic Oligonucleotide; delivery system

Parenteral miR-150 Texas A&M Oligonucleotide treatment of leukemia

University

System

SCN9A inhibitor OliPass Injectable; Peptide mRNA of SCN9A, an i so type selective sodium (injectable Corporation Oligonucleotide; channel, for the potential treatment of neuropathic Parenteral neuropathic pain

pain), OliPass

HIF-1 alpha OliPass Injectable; peptide nucleic acid-based oligonucleotide, blocker Corporation Oligonucleotide; which blocks hypoxia-inducable factor (IIIF) 1

(injectable Parenteral alpha, for the potential injectable treatment of cancer), cancer

OliPass

MTL-301 MiNA Injectable; type I diabetes

Therapeutics Oligonucleotide;

Ltd Parenteral

antisense Isis Oligonucleotide WO20150389 complement factor B (CFB) and component 5, oliqonucleotides Pharmaceutic antisense 39 for the potential treatment of renal diseases (renal disease), a Is

Isis

Pharmaceutical

s

exon-skippinq University Oligonucleotide; hypercholesterolemia

antisense College Parenteral

oliqonucleotides London

(hvpercholester

olemia),

University

Colleqe London

antisense Isis Oligonucleotide Parkinson's disease

oliqonucleotides Pharmaceutic antisense

(Parkinsons als

disease), Isis

Pharmaceutical

s

NFkappaB AnGes MG Injectable; NFkappaB decoy oligonucleotide program, decov Oligonucleotide; which stimulates prostaglandin synthesis and oliqonucleotide Parenteral inhibits degradation of prostaglandins in facet proqram joint cartilage, for the injectable treatment of

(iniectable osteoarthritis

osteoarthritis),

AnGes

ISIS-GSK4-LRX Isis Oligonucleotide antisense drug for the potential treatment of an

Pharmaceutic antisense; ocular disease

als Parenteral

ALN-ANG AInyiam Oligonucleotide; RNAi therapeutic which targets angiopoietin- Pharmaceutic Subcutaneous like 3 (ANGPTL3), using GalNAc-siRNA als conjugate delivery technology, for the potential sc treatment of genetic forms of mixed hyperlipidemia, including hypertriglyceridemia.

D-l 92935 Oregon Oligonucleotide toll-like receptor 9 (TLR9) agonists which

Health comprises three different single-stranded Sciences synthetic DNA CPG oligonucleotides (ODNs), University for potential use in the prophylactic treatment of cerebrovascular ischemia

beta-catenin Yale Oligonucleotide antisense oligonucleotide (ASO) targeting antisense University antisense beta-catenin, for the potential treatment of nonoliqonucleotide alcoholic fatty liver disease and type II (non-alcoholic diabetes

liver

disease and

tvpe II

diabetes), Yale

University

CD5-2 Mirrx Oligonucleotide; WO20140530 15-mer oligonucleotides that selectively inhibit

Therapeutics Oligonucleotide 14 miR-27a vascular endothelial cadheriii-5 ( VE- (CICMCB) antisense cadherin) regulation and promoting

angiogenesis, using Mirrx' Blockmir technology, for the potential treatment of vascular permeabi lily-deficient diseases including ischemia, inflammation, oedema and solid tumors

miR-135b Academia Nanoparticle; chemically modified antisense RNA

antaqomir Siiiica Oligonucleotide; ; oligonucleotide against miR-135b (intronic

PEGylated; RNA miRNA), for the potential treatment of NSCLC antisense

siRNA targeting University of Oligonucleotide; siRNA targeting six-1 which acts by inhibiting six-1 Colorado Parenteral; RNA cyclin Al activity, for the potential treatment

System technology of cancer

RRM1 -specific EnGeneIC Pry Oligonucleotide RRM1 -specific siRNA for the potential siRNA Ltd treatment of malignant pleural mesothelioma antisense IRF-4 Isis Oligonucleotide generation -2.5 antisense oligonucleotides oligonucleotides Pharmaceutic antisense targeting -interferon regulatory factor-4 (IRF-4) als for the potential treatment of multiple myeloma

TKM-GSD Tekmira Liposome; siRNA therapeutics delivered by Tekmira's

Pharmaceutic Nanoparticle; lipid nanoparticle (LNP) technology, for the als Corp Oligonucleotide; potential treatment of glycogen storage disease

Parenteral type fV

microRNA University of Diagnostic US- microRNA therapy for the potential diagnosis therapy Colorado method; 20140274923 and treatment of pediatric heart failure.

System Oligonucleotide;

Parenteral

PRX-MET PhaseRx Nanoparticle; WO20141097 siRNA therapeutic that inhibits MET and by

Oligonucleotide; 80 which inhibits the oncogene expression in

Parenteral tumor ceils, developed using its proprietary

SMAR.TT Polymer Technology (S!VIARTT) platform to deliver mRNA nanoparticles to the liver and for the potential treatment of hepatocellular carcinoma (HCC)

anti-miR- Regulus Oligonucleotide anti-miR-221/222 antisense oligonucleotides 221/222 Therapeutics / antisense (miR-221/222) for the potential treatment of antisense Sanofi hepatocellular carcinoma.

oligonucleotide

antisense Hypogen Oligonucleotide antisense therapy for the potential treatment of therapy antisense essential hypertension.

Prospect Prosensa Oligonucleotide antisense oligonucleotide designed to target

Therapeutics antisense; rarer mutations and induce multiple skipping

BV Parenteral for exons 10-30 of the dystrophin gene, for the potential treatment of Duchenne muscular dystrophy

miR-30c mimics SUNY Oligonucleotide mimics of microRNA (miR)-30c, an

Downstate microsomal triglyceride transfer protein

Medical (MTTP) gene inhibitor that reduces fat in

Center blood circulation and decreases lipid synthesis, for the potential treatment of atherosclerosis and hyperlipidernia

NOX-G16 NOXXON Oligonucleotide; PEGylated, glucagon-targeting, DNA-based

Pharma AG PEGylated spiegelmer of NOX-G15, for the potential treatment of type 1 and 2 diabetes.

anti-miRNA-145 EGEN Nanoparticle; anti-miRNA-145, based on the EGEN's lung

(Celsion Oligonucleotide targeting staramine-mPEG nanoparticle

Corp) delivery system, TheraSilence, for the potential treatment of pulmonary arterial hypertension (PAH)

SRP-4050 Sarepta Oligonucleotide WO20100485 phosphorodiamidate morpholino oligomer

Therapeutics antisense; 86 (PMO)-based antisense RNA therapeutic,

Parenteral targeted to skip dystrophin gene exon 50, for the potential treatment of Duchenne muscular dystrophy (DMD)

ahFR-tarqeted National Oligonucleotide antisense oligonucleotides that selectively antisense Cancer antisense targets and diminishes the levels of human oliqonucleotides Institute alpha, folate receptor (ahFR), for the potential treatment of cancer

siRNAs Johns Oligonucleotide; siRNAs, which inhibit HCV replication, for the

Hopkins Parenteral potential prevention of recurrence of HCV

University infection after liver transplantation and for the potential treatment of HCV infection

E6 qene National Oligonucleotide antisense oligonucleotides with

tarqettinq Cancer antisense phosphorothioate backbone structure, targeting antisense Institute E6 gene of human papilloma virus-16 (HPVl 6) oliqonucleotide for the potential treatment of HPV infection.

GIBH-R-001 -2 Guangzhou Intra-articular; TNF-alpha, ADAMTS-5 and RHAAM-

Institutes of Nanoparticle targeting siRNA conjugated with positively Biomedicine injectable; charged nanoparticles, for the potential intraand Health Oligonucleotide articular treatment of osteoarthritis (OA) and rheumatoid arthritis (RA)

oliqodeoxvnucle Yokohama Oligonucleotide oiigodeoxynucieo tides (ODN) expressing poly- otides City G motifs, as IL-2 upregulators, for the potential expressinq University treatment of cancer

polv-G motif NCI/Tohoku

University

miRNA mimics National Eye Oligonucleotide; anti-miRNAs and miRNA mimics, specifically

Institute Parenteral directed against miRNA 204 and miRNA 21 1 , for the potential treatment and prevention of age-related macular degeneration (AMD) and other eye -related diseases including proliferative vitreal retinopathy, neovascular disease and carcinoma.

osteopontin Eunice Oligonucleotide osteopontin inhibiting antisense

inhibitinq Kennedy antisense; oligonucleotides, for the potential treatment of antisense Shrivei" Parenteral restenosis.

oliqonucleotides NICHD

CDM- Arrowhead Nanoparticle; modified PEG-carboxylated dimethyl maleic coniuqated Research Oligonucleotide anhydride (CDM)- conjugated siRNA siRNA polymers Corp conjugated; polymers, developed using the dynamic

PEGylated polyconjugate (DPC) technology, for the potential treatment of cancer.

PNT-600 ProNAi Oligonucleotide ProNAi is investigating PNT-600, UNA

Therapeutics interference (DNAi) therapy which targets IL- 8, for the potential treatment of cancer and inflammation

PNT-500 ProNAi Oligonucleotide DNA interference (DNAi) therapy which

Therapeutics targets STAT3, for the potential treatment of cancer

PNT-400 ProNAi Oligonucleotide DNA interference (DNAi) therapy, which

Therapeutics targets surviviii, for the potential treatment of cancer

STAT-4 NIAID Oligonucleotide STAT-4 antisense oligonucleotide, which antisense antisense; inhibits the STAT-4 pathway, for the potential oliqonucleotide Parenteral treatment of Crohn's disease and colitis antisense National Oligonucleotide antisense oligonucleotides targeting niRNA oliqonucleotides Cancer antisense; encoding basic fibroblast growth factor, for the

Institute Parenteral potential treatment of Kaposi's sarcoma in patients with ITPV-I

ISIS-HTTRx Isis Oligonucleotide an antisense oligonucleotide (ASOs) that

Pharmaceutic antisense; blocks all forms of the huntingtin (HTT) als Systemic protein, using Isis' ASO technology, for the potential treatment of Huntington's disease (HD)

stathmin RNAi National Oligonucleotide; RNAi oligonucleotides, that down regulate oliqonucleotides Institute of Parenteral; RNA stathmin expression, for the potential treatment

Neurological technology of cancer including leukemias, lung cancers Disorders and and brain tumors

Stroke

AMG-0103 AnGes MG Injectable; NF-kappaB decoy oligodeoxyniicleotide, an

Oligonucleotide; anti -inflammatory agent for the potential

Parenteral injectable treatment of lumbalgia including discal herniation (degeneration)

RBT-08 Rodos Nanoparticle; siRNA agent encapsulated using its

BioTarget Oligonucleotide TargoSphere technology, for the potential

GmbH treatment of an undisclosed indication

QR-010 ProQR Oligonucleotide WO201401 10 antisense oligonucleotide targeting the CFTR

Therapeutics antisense; RNA 53 F5()8delta mutation for the potential treatment

BV antisense of cystic fibrosis (CF)

oliqonucleotides National Oligonucleotide antisense and sense oligonucleotides targeting tarqetinq the Human antisense; the RNAs of endogenous retro virus-9 (ERV-9) RNAs of ERV-9 Genome Parenteral long terminal repeats (LTR), for the potential LIB Research treatment of cancers including human breast,

Institute liver, prostate, and myeloid cancers and

fibrosarcomas

CD45 inhibitor Virogenics Nanoparticle; siRNA agent, which inhibits CD45, delivered

Oligonucleotide using a nanoparticle, for the potential treatment of infectious diseases caused by biot reatening pathogens

MTL-01 1 MiNA Oligonucleotide; injectable saRNA therapeutic activating an

Therapeutics Parenteral undisclosed gene, for the potential treatment of

Ltd type 2 diabetes

ASPH-1047 Isarna Intratumoral; WO20141548 oligonucleotide TGF-beta 1 inhibitor, for the

Therapeutics Oligonucleotide 35 potential intratumoral treatment of cancer GmbH

miR-126 Cooperative Oligonucleotide modified antisense oligonucleotide that inhibits inhibitor Research antisense miR-126 (anti-miR-126), for the potential

Centre for treatment of respiratory diseases such as Asthma and asthma, COPD and allergic rhinitis

Airways antisense Cooperative Oligonucleotide WO20090558 antisense oligonucleotide that inhibits fibulin- oliqonucleotide Research antisense 64 1C, for the potential treatment of asthma

Centre for

Asthma and

Airways

antisense Isis Oligonucleotide WO20140363 antisense oligonucleotides against copper oliqonucleotides Pharmaceutic antisense 01 transporter 1 (CTR1) for the potential

als treatment of Wilson disease antisense Isis Oligonucleotide antisense oligonucleotides (ASOs) to suppress oliqonucleotides Pharmaceutic antisense androgen receptor full length (AR(fl)) and als known AR splice variants in enzalutamide- resistant castration-resistant prostate cancer (CRPC)

PRC2-tarqetinq RaNA Oligonucleotide; oligonucleotides that act by blocking polycomb

Therapeutics Subcutaneous repressive complex 2 (PRC2), for the potential sc treatment of genetic, cardiovascular , metabolic, neurodegenerative, muscular and hematologic diseases

siRNA therapy Biomics Oligonucleotide siRNA therapy for the potential treatment of

Biotechnologi psoriasis

es (Nantong)

Co Ltd

nanoRNA Lakewood- Oligonucleotide small inhibitory RNA molecules that therapeutic Amedex selectively bind to the messenger RNA of a target gene, for the potential treatment of seasonal influenza, virus infection including avian ^'influenza and swine influenza.

FOXO-1- Lakewood- Oligonucleotide; nanoRNA therapeutic targeting Forkhead box tarqetinq Amedex Parenteral protein 01 (FOXO-1), which utilizes small inhibitory RNA molecules that selectively bind to the messenger RNA of a target gene, for the potential treatment of muscle wasting nanoRNA Lakewood- Oligonucleotide; nanoRNA therapeutic, which utilizes small therapeutic Amedex Parenteral inhibitory RNA molecules that selectively bind to the messenger RNA of a target gene, for the potential treatment of hepatitis B virus infection

ALN-AS1 Alnylam Oligonucleotide; WO20131552 RNAi therapeutic, targeting aminolevulinate

Pharmaceutic Subcutaneous 04 synthase 1 (ALAS-1 ), using its GalNAc- als siRNA conjugate technology, for the potential sc treatment of acute intermittent porphyria (AIP)

GNKS-356 Changchun Oligonucleotide nucleic acid therapy, GNKS-356, a

Huapu plasmacytoid dendritic cell inhibitor that

Biotechnolog supresses TLR-9 function, for the potential y Co Ltd treatment of B-cell chronic lymphocytic leukemia and autoimmune disease

ISIS- Isis Oligonucleotide TMPRSS6 expression-targeting antisense

TMPRSS6-LRX Pharmaceutic antisense; oligonucleotides (ASOs) for the potential als Parenteral treatment of hereditary hemochromatosis and beta-thalassemia

DsiRNAs- Dicerna Oligonucleotide WO20130326 Dicer-substrate siRNAs (DsiRNAs) that target tarqetinq beta Pharmaceutic 43 beta-catenin, for the potential treatment of catenin als cancer

KHK-3 Dicerna Oligonucleotide formulated using Dicema's proprietary Dicer

Pharmaceutic Substrate Technology and Kyowa's proprietary ais delivery system, for the potential treatment of multiple cancers

KHK-2 Dicerna. Oligonucleotide formulated using Dicerna's proprietary Dicer

Pharmaceutic Substrate Technology and Kyowa's proprietary als delivery system, for the potential treatment of multiple cancers

LSP-GR1 LifeSplice Oligonucleotide AMP A receptor splice modulating oligomer

Pharma LLC an ti sense; (SMO) that reduces GluRl flip expression, for

Parenteral the potential treatment of epilepsy in adults and infants and amyotrophic lateral sclerosis

GluR3 splice LifeSplice Oligonucleotide AMP A receptor splice modulating oligomers modulatinq Pharma LLC anti sense; (SMOs) that reduce GluR.3 flip expression, oliqomers Parenteral including lead SMO LSP-GR3, for the

potential treatment of amyotrophic lateral sclerosis (ALS)

MT-004 ModeRNA Oligonucleotide; mRNA therapeutic, for the potential use as a

Therapeutics Parenteral cancer supportive care

uqimers Ugichem Oligonucleotide gene silencing therapeutic program for the

GmbH potential treatment of immune and

inflammatory disorders incuding rheumatoid arthritis

ASPH-0047 Isarna Intravenous; next generation antisense oligonucleotide TGF-

Trabedersen Therapeutics Oligonucleotide beta 2 inhibitor, for the potential iv treatment

GmbH anti sense of cancer

ALN-AAT Alnyiam Nanoparticle WO20141901 siRNA agent that targets the mutant Z-allele in

Pharmaceutic injectable; 37 alpha- 1 -antitrypsin ( AT) deficiency, created als Oligonucleotide; using Alnylam's GalNAc conjugate technology

Subcutaneous and formulated in a lipid nanoparticle, for the potential sc treatment of liver disease associated with AAT deficiency

SAMiRNA Bioneer Corp Nanoparticle; WO20150025 Self-Assembled-Micelie-inhibitory-RNA roqram Oligonucleotide; 12 (SAMiRNA) technology, for the potential

Prodrug treatment of viral infections

SAMiRNA Bioneer Coip Nanoparticle; WO20150025 Self-Assembied-Micelle-inhibitory-RNA roqram Oligonucleotide; 13 (SAMiRNA) technology, for the potential (COPD/ IPF), Prodrug treatment of COPD and idiopathic lung fibrosis Bioneer (IPF)

SAMiRNA- Bioneer Corp Nanoparticle; WO20130895 siRNA-based prodrug developed using the survivin (solid Oligonucleotide; 22 company's Self-Assembled-Micelle-inhibitory- tumor), Bioneer Prodrug RNA (SAMiRNA) technology, for the

potential treatment of solid tumors oliqonucleotides OP O Health Oligonucleotide oligonucleotides, which up-regulate a targeted antisense gene through the inhibition of Natural

Antisense Transcripts (NATs), using AntagoNAT technology, for the potential treatment of Rett syndrome

STP-909 Simaomics Nanoparticle; histidine-lysine co-polymer nanoparticle- Oligonucleotide formulated siRNA duplex therapeutic that silences viral protein expression, for the potential treatment of human papillomavirus strain 16 and 18 (HPV 16, HP VI 8) infection and the prevention of cervical cancer siRNA stromal 1NSERM Oligonucleotide WO09124973 stromal interaction molecule 1 (STI l) siRNA interaction inhibitors for the potential treatment of molecule 1 cardiovascular disorders

inhibitors ATP-00001 AdiuTide Injectable; CpG oligodeoxynucleotide (CpG ODN) with a. Pharmaceutic Oligonucleotide; chemical modification at the CpG motif, for ais GmbH Parenteral the potential injectable treatment of cancer

Toca-RNAi Tocagen Oligonucleotide; WO20142014 siRNA therapeutic and a retroviral replicating

Paren teral ; V ini s 49 vector with one or more RNAi genes, recombinant developed using the company's controlled active gene transfer (CAGT) vector technology, for the potential treatment of cancer

NLF-PD-1233 nLife Oligonucleotide WO20140642 neuronal specific oligonucleotides (nOligos),

Therapeutics antisense; 57 targeting alpha-synuclein, developed using its SL Parenteral oligonucleotide delivery platform, for the potential treatment of Parkinson's disease (PD)

NanoSi-CD-36 Qua liber Liposome; nanoparticle liposomal of NanoSi-CD-36, a

Nanoparticle; siRNA-based agent, for the potential treatment

Oligonucleotide of an undisclosed indication

Atu-614 Silence Lipid; sirNA therapeutic, presumed to be Atu-614,

Therapeutics Oligonucleotide; that inhibits Fas receptor, using the lipid-based pic Parenteral; DBTC-siRNA delivery system for RNAi of

Systemic undisclosed targets, for the potential treatment of acute and paracetamol -induced liver failure

BN-210 Bionucieon Oligonucleotide WO20091499 ap tamer comprised of 33-mer oligonucleotides

Sri conjugated; 21 fused to PEG 20-kDa and the lead from the

PEGylated series of aptamers that inhibits Pro-Tyr-Tyr- Pro (PWWP) domain of hepatoma-derived growth factor related protein-3 (HRP-3), for the potential treatment of cancer including neuroblastoma, NSCLC, melanoma, colon, kidney, and lung cancer

mRNA-MD1 Marina Oligonucleotide; single-stranded oligonucleotide construct,

Biotech Parenteral targeting the CUG repeat in mRNA for the dystrophia myotonica-protein kinase (DMPK.) gene, for the potential treatnient of myotonic dystrophy

TKM-ALDH Tekmira Liposome; WO20130526 RNAi therapeutic that targets aldehyde

Pharmaceutic Nanoparticle 77 dehydrogenase^ (ALDFI2), using the als Corp injectable; company's lipid nanoparticle (LNP) deliver}'

Oligonucleotide technology, for the potential injectable

treatment of alcohol dependence antibacterial Procarta Antibiotic; oligonucleotide therapeutic which blocks compounds Biosystenis Nanoparticle; expression of targeted, essential bacterial genes

Ltd Oligonucleotide and a bacterial -spec! tic nanoparticle delivery system, for the potential oral treatment of MRSA infection

SIRNAPLUS Polyplus Local; cationic siRNA duplexes, composed of an

Transfection Oligonucleotide antisense sequence annealed to an

SAS oligospermine conjugated sense strand, as systemic and local s, for the potential treatment of cancer

STICKY SIRNA Polyplus Oligonucleotide; STICKY SIRNA (ssiRNA) therapeutics

Transfection Parenteral comprising interfering RNAs combined with

SAS the in vivo jetPE! technology, a cationic linear polyethylenimine (PEI) delivery reagent, for the potential treatment of cancer

Napa-001 NapaJen Oligonucleotide Napa-001 inhibits macrophage migration

Piiarma. antisense; inhibitory factor (MIF), delivered using

Parenteral company's NapaJen technology, for the potential treatment of autoimmune disorders including rheumatoid arthritis (RA) and ulcerative colitis (UC)

STP-916 Sirnaomics Oligonucleotide; siRNA therapeutic, for the potential treatment

Parenteral of liver cancer

STP-91 1 Sirnaomics Oligonucleotide; WO20120161 siRNA therapeutic, for the potential treatment

Parenteral 39 of human papillomavirus (HPV) infection and cancer, presumably cervical cancer

NOX-G15 NOXXON Injectable; glucagon-targeting spiegelmer, for the

Pfaarma. AG Oligonucleotide potential iv or sc treatment of diabetes mellitus including type 1 and 2 diabetes

SB-021 sterna DNA technology; DNAzyme antisense oligonucleotide, which biologicals Inhalant; targets Tbet, for the potential inhalational

GmbH and Co Oligonucleotide treatment of COPD

KG anti sense

SB-020 sterna DNA technology; DNAzyme antisense oligonucleotide, which biologicals Oligonucleotide targets Tbet and directly inhibits Thl cell GmbH and Co antisense activation and subsequent inflammatory KG mechanisms, for the potential treatment of psoriasis

Srpx2 inhibitors Clayton Oligonucleotide; WO20091 1 14 siRNA therapeutics targeting against Srpx2 for

Foundation Parenteral 44 the potential treatment of cancer

For Research

ALN-TMP Alnylam Liposome; WO20121352 a lipid nanoparticle (LNP)-formulated siRNA

Pharmaceutic Nanoparticle; 46 targeting the Tmprss6 (transmembrane serine als Oligonucleotide protease 6) gene, whose gene product cleaves hemojuvelin, resulting in elevated hepcidin levels and reduced iron mobilization, for the potential treatment of hereditary hemochromatosis, beta-thaJassemia and other disorders involving iron overload, including hemoglobinopathies and sickle cell anemias

SRP-4045 Sarepta Oligonucleotide follow-on compound of eteplirsen and a.

Therapeutics antisense; RNA phosphorodiamidate morpholino oligomer antisense (PMO) -based antisense RNA therapeutic, targeted to skip dystrophin gene exon 45, for the potential treatment of Duchenne muscular dystrophy (DMD)

NLF-MO nLife Nanoparticle; WO20140642 a central appetite modulator targeting

Therapeutics Oligonucleotide 58 suppressor of cytokine signalling-3 (SOCS3) SL antisense; and protein tyrosine phosphatase- 1 B (PTPib)

Parenteral in hypothalamic AGRP+ neurons, and the lead from a series of next generation nanotherapeutics, for the potential treatment of morbid obesity

be NLF-NEU nLife Nanoparticle; neuronal specific oligonucleotide (nOligos) (NLF-MDD; Therapeutics Oligonucleotide targeting 5-HTl a or serotonin reuptake in NLF- 10808 SL antisense; seratonergic neurons and the lead from a series

Oligosaccharide; of siRNA nanotherapeutics, for the potential treatment of major depression disorders

PCSK9 qene- Idera Oligonucleotide gene-silencing oligonucleotides (GSOs) that silencinq Pharmaceutic antisense target proprotein converta.se subtilisin/kexin oliqonucleotides als type 9 (PCSK9) rriRNA for the potential treatment of hypercholesterolemia

ApoB qene- Idera Oligonucleotide gene-silencing oligonucleotides (GSOs) that silencinq Pharmaceutic antisense target apo lipoprotein B (ApoB) mRNA for the oliqonucleotides ais potential treatment of hypercholesterolemia.

ISIS-AATRx Isis Oligonucleotide WO20131425 ISIS-AATRx, an antisense compound designed

Pharmaceutic antisense 14 to inhibit production of the abnormal alpha- i als / GSK. antitrypsin (ATT) protein for the potential treatment of liver disease caused by ATT deficiency

PC-91 ProCell Monoclonal cerul op lasmin-m Ab (CP-mAb) conjugated

Therapeutics antibody siRNA, PC-91, which acts as an angiogenesis conjugated; inhibitor, developed using the company's

Oligonucleotide; macromolecular intracellular transduction

Parenteral technology (MITT), for the potential treatment of an undisclosed indication

GND-007 Gene Techno Oligonucleotide; siRNA therapeutic for the potential treatment

Science Co Parenteral of cancer and immune diseases

Ltd

TKM-HepC, SG- Tekmira Lipid; shRNAs including TKM-HepC, SG-220, SG-

220, SG-237 and Pharmaceutic Nanoparticle; 237 and SG-273 targeting reporter HCV- SG-273 als Corp / Oligonucleotide internal ri bo some entry site (IREs)-fLuc,

Somagenics, delivered using Tekmira' s lipid nanoparticle

Roche (LNP) technology, for the potential treatment of hepatitis C virus infection

oliqonucleotide OPKO Health Oligonucleotide WO20120547 AntagoNAT technology platform, an alpha-L- 23 oligonucleotide to target a. non-coding natural iduronidase antisense transcript on the alpha-L-iduronidase

(IDUA) gene in order to upregulate it for the potential treatment of mucopolysaccharidosis type I (MPS I)

apoBlOO SynBio LLC Drug SynBio, incorporating a product obtained from combination; Symbiotec, is investigating SYN-

Oligonucleotide; 201101 19RU, recombinant human histone

Parenteral HI .3 (Oncohist), in combination with siRNA apoBlOO, for the potential treatment of atherosclerosis

oliqotide Gentium SpA Oligonucleotide WO20060949 oligonucleotide that inhibits heparana.se

Jazz 16 expression, for the potential treatment of renal

Pharmaceutic disease, including diabetic nephropathy als

ABS-393 Apama Nanoparticle; targeted anti-VEGFR2 siRNA nanoparticle,

Biosciences Oligonucleotide; developed using the company's

Coip Parenteral NanoElectroPlex technology, for the potential treatment of cancer including NSCLC siRNA Galena. Oligonucleotide; WO20131771 siRNA therapeutics, created using sd-rxRNA therapeutics Biopharma Ophthalmic 94 technology and targeted to cyclophilin B and

RXi MAP4K4 production, for the potential

Pharmaceutic treatment of ocular diseases, including age- alsl related macular degeneration (AMD) and retinoblastoma and presumed to be for dermatological diseases

RG-125 Regulus Oligonucleotide GalNAc-conjugated anti microRNA

Therapeutics oligonucleotides, which antagonize

AstraZeneca microRNA-103 (miR-103) and microRNA- 107

(miR-107), for the potential treatment of metabloic diseases including non-alcoholic steatohepatitis (NASH), diabetes and obesity inhibitory RNA EGEN Intravenous; siRNA's or/and shRNA's including (GEN-2; aqents GEN-2; Celsion Corp Oligonucleotide EGEN-002; EGEN-RNA-002), based on EGEN-002; EGEN's TlieraSilence RNAi delivery platform, EGEN-RNA- for the potential intravenous treatment of 002 cancer including lung cancer

STP-801 Sirnaomics Nanoparticle; nanoparticle of siRNA combination targeting

Oligonucleotide; EGFR, VEGF and CO -2 genes, for the

Parenteral potential treatment of NSCLC

STP-902 Sirnaomics Oligonucleotide; mul ti -targeted siRNA therapeutic cocktail, for

Parenteral the potential treatment of RSV infection

STP-805 Sirnaomics Nanoparticle; nanoparticle of multi-targeted siRNA

Oligonucleotide; therapeutic cocktail, for the potential treatment

Parenteral of spinal cord injury

STP-523 Sirnaomics Nanoparticle; WO20091515 nanoparticle of siRNA therapeutic

Oligonucleotide; 39 combination that targets the angiogenesis

Parenteral genes EGFR and VEGF, and 06- methyiguanine-DNA-methlytransferase (AGT), involved in resistance of GBM cells to drags such as temozolomide, for the potential treatment of glioblastoma multiforme (GBM).

PAX2-tarqetinq Phigenix Oligonucleotide; siRNA therapeutics that inhibit paired box siRNA Parenteral protein (PAX)-2 leading to the re-expression of therapeutics beta defensin-1 (DEFB-1 ), for the potential treatment of prostate

SCN1A protein 0PK.0 Health Oligonucleotide oligonucleotides, which up-regulate a targeted stimulator antisense gene through inhibition of Natural Antisense oliqonucleotides Transcripts (NATs) to increase endogenous

SCN1A (sodium channel) protein production, using its AntagoNAT technology platform for the potential treatment of Dravet syndrome (severe myoclonic epilepsy of infancy) siRNA Samyang Oligonucleotide; WO201 10814 polymeric micelle of siRNA therapeutics, for therapeutics Corp Parenteral; 15 the potential treatment of cancer

Sustained release

GS-10 GeneSegues Nanoparticle; tenfibgen-nanocapsule of RNAi therapeutic,

Therapeutics Oligonucleotide; which inhibits casein kinase-2, for the potential

Parenteral treatment of cancer i cluding head and neck, prostate, breast cancers and other solid tumors siRNA micelle NanoCarrier Intravenous; WO20080629 sustained release, nanoparticle of siRNA

Co Ltd Nanoparticle 09 therapeutic, based on NanoCap technology,

Oligonucleotide licensed from the University of Tokyo, for the antisense; potential iv treatment of an undisclosed

indication

BIOO-7 BIOO Monoclonal mAb-conjugated siRNA, based on the BIOO

Therapeutics antibody Scientific's proprietary drug delivery

conjugated; technology, for the potential treatment of aging Oligonucleotide

BIOO-4 BIOO Monoclonal mAb-conjugated siRNA, based on the BIOO

Therapeutics antibody Scientific's proprietary drag delivery

conjugated; technology, for the potential treatment of aging Oligonucleotide

BIOO-6 BIOO Oligonucleotide; mAb-conjugated siRNA, based on the BIOO

Therapeutics Parenteral Scientific's proprietary drag delivery

technology, for the potential treatment of cancer

BIOO-5 BIOO Oligonucleotide; mAb-conjugated siRNA, based on the BIOO

Therapeutics Parenteral Scientific's proprietary drug delivery

technology, for the potential treatment of cancer, including melanoma BIOO-3 BIOO Oligonucleotide; mAb-conjugated siRNA, based on the BIOO

Therapeutics Parenteral Scientific's proprietary drag delivery

technology, for the potential treatment of cancer including melanoma and breast cancer

BIOO-2 BIOO Oligonucleotide; mAb-conjugated siRNA, based on the BIOO

Therapeutics Parenteral Scientific's proprietary drug delivery

technology, for the potential treatment of cancer including ovarian cancer

BIOO-1 BIOO Oligonucleotide; mAb-conjugated siRNA, based on the BIOO

Therapeutics Parenteral Scientific's proprietary drug delivery

technology, for the potential treatment of cancer including breast and lung cancer

EVIRNA NanoOncol og Nanoparticle; WO201 1 1469 siRNA agent that inhibits the E I1 gene, using y Oligonucleotide; 38 the company's nanoparticle drug delivery

Parenteral system hELP, for the potential treatment of ovarian cancer and other cancers, including melanoma, prostate, colon, lung and breast cancers

aqanirsen Gene Signal Nanoparticle; nanomolecule of aganirsen (GS-101), an

SAS Oligonucleotide insulin receptor substrate- 1 (IRS- 1 ) -inhibiting antisense antisense oligonucleotide and angiogenesis inhibitor, for the potential treatment of bladder cancer

STNM-04 Stelic Institute Oligonucleotide siRNA targeting G-family glycogene 4, for the

& Co potential treatment of liver cirrhosis (LC) and pulmonary fibrosis

FGFR4 University of Oligonucleotide antisense oligonucleotides (Fat Blockers), antisense Queensland antisense which prevent fat formation, for the potential oliqonucleotides Verva treatment of obesity

miRNA-based InteRNA Oligonucleotide; WO20140723 miRNA-based therapeutics targeting B-Raf, therapeutics Technologies Parenteral 57 including mimics of miRNA-3157 (miR-3157),

BV for the potential treatment of melanoma chitosan-siRNA enGene Nanoparticle; WO20150427 chitosan-siRNA nanoparticles targeted at gut nanoparticles Oligonucleotide; 1 1 tissue, created using enGene' s gut epithelial-

Parenteral cell modification system (GEMS) technology, for the potential treatment of colorectal cancer anti-miR-10b Regulus Oligonucleotide antisense oligonucleotide inhibitors of the antisense Therapeutics antisense; microRNA miR-10b for the potential treatment oliqonucleotides Parenteral of metastases, especially arising from breast cancer and glioblastoma

MCT-485 MultiCell Oligonucleotide low molecular weight synthetic

Technologies noncoding double-stranded miRNA with tumor cytolytic properties and which stimulates the production of TNF-alpha by tumor cells, for the potential treatment of cancer including primary liver cancer and triple negative breast cancer

BO-110 folC- Bioncotech Injectable; WO201 10038 dsRNA mimic polyinosine-polycytidylic acid PEI) Therapeutics Oligonucleotide 83 (pIC) complexed with polyethyleneimine (PEI)

SL conjugated; as a polycationic carrier for cytosolic delivery,

Parenteral which activates the lielicase MDA-5 and leads to stimulation of autophagy, apoptosis and immune response, for the potential injectable treatment of cancer including melanoma, glioblastoma, pancreatic and bladder cancer

MGN-1374 miRagen Oligonucleotide; miR-15/miR-195 targeted antisense Therapeutics / Parenteral oligotherapeutics, using Santaris Pharma's Les Locked Nucleic Acid (LNA) Drug Platform,

Laboratoires for the potential treatment of post myocardial

Sender infarction (MI)

MGN-6114 niiRagen Oligonucleotide; WO20090124 miR-92 inhibitor using Santaris Pharma's

Therapeutics Parenteral 68 Locked Nucleic Acid (LNA) Drag Platform, for the potential treatment of peripheral artery disease (PAD)

MGN-4220 niiRagen Oligonucleotide; miR-29 mimetic for the potential treatment of

Therapeutics Parenteral fibrosis including cardiac and idiopathic pulmonary fibrosis

NOX-S93 NOXXON Spiegelmer WO201 1 1313 spiegelmer targeted to sphingosine-1-

Pharrna AG 71 phosphate (SIP) including NOX-S91, for the potential treatment of cancer

PU-27 University of Oligonucleotide synthetic quadruplex DNA oligonucleotide

Louisville antisense which comprises a part of c-Myc oncogene,

Advanced using Terigo platform, for the potential

Cancer treatment of cancer

Therapeutics

MGN-9103 niiRagen Oligonucleotide WO20120830 miR-208/miR-499 inhibitor, MGN-9103

Therapeutics / antisense; 04 (MIRG-9103), a single-stranded antisense Les Parenteral oligonucleotide, using Santaris Pharma's

Laboratoires Locked Nucleic Acid (LNA) Drug Platform, Servier for the potential treatment of chronic heart failure

PRO-055 Prosensa. Oligonucleotide single-stranded RNA-based antisense

Therapeutics antisense; oligonucleotide-based therapy designed to skip

BV Parenteral; RNA exon 55 of the dystrophin gene, for the

antisense potential treatment of Duchenne muscular dystrophy (DMD)

TBL-0404 Transgene Oligonucleotide; WO201 1 1018 mi RNA-based vector system agent, delivered

Biotek Ltd Parenteral 69 through company's proprietary adeno- associated virus technology (AAV), for the potential treatment of hepatocellular carcinoma mRNA-BC Marina Intravesical; WO00050062 DiLA2 lipo some-formula ted UsiRNA program

Biotech Liposome; targeting polo-like kinase 1 (PLK1), including

Oligonucleotide Debio-1 141 , using Marina's tauRNAi

technology, for the potential treatment of cancer, including non-muscle invasive bladder cancer

PRO-289 Prosensa. Oligonucleotide WO20120182 single-stranded RNA-based antisense

Therapeutics antisense; 57 oligonucleotide-based therapeutic to inhibit the

BV Parenteral; RNA CTG trinucleotide repeat expansion of

antisense huntingtin gene (HTT) for the potential treatment of Huntington's disease (HD)

PRO- 135 Prosensa Oligonucleotide WO20121449 single-stranded RNA-based antisense

Therapeutics antisense; 06 oligonucleotide designed to inhibit the CUG

BV Parenteral; RNA trinucleotide repeat expansion of dystrophia antisense myotonica -protein kinase (DMPK) gene, for the potential treatment of myotonic dystrophy- type 1 (DM1 )

PRO-052 Prosensa Oligonucleotide WO20090547 antisense oligonucleotide-based therapy

Therapeutics antisense; 25 designed to skip exon 52 of the dystrophin

BV Parenteral gene for the potential treatment of Duchenne muscular dystrophy

RX-0201-N Rexahn Nanoparticie; WO2013 1774 nanoiiposomal of RX-0201 as an antisense (RX-0201 -nano; Pharmaceutic Oligonucleotide 15 oligonucleotide inhibitor of the AK.T-1 protein Archexin-N) als antisense; kinase gene, for the potential treatment of cancer

Adva-R46 Advanomics Oligonucleotide; interferring RNA (RNAi) therapeutic, for the

Corp Parenteral potential treatment of cancer

GLi2 RNA Roche Oligonucleotide WO20100075 locked nucleic acid (LNA) antisense antaqonist Innovation antisense 22 oligonucleotide -based GLi2 RNA antagonists,

Center including EZN-4482 and EZN-4496, for the

Copenhagen potential treatment of cancer

A/S

beta-catenin Roche Oligonucleotide WO20081322 Locked Nucleic Acid (LNA) antisense mRNA Innovation antisense; 34 oligonucleotide beta-catenin mRNA antaqonists Center Parenteral antagonist, including EZN-3889 and EZN-

Copenhagen 3892, for the potential treatment of cancer

A/S

complement NOXXON Injectable; WO20101086 spiegelmer-based inhibitors of complement factor C5a Pharma AG Parenteral; 57 factor C5a, including NOX-D20, NOX-D19, inhibitors Spiegelmer NOX-D 15 , NOX-D 14 and NOX-D21 , for the potential injectable treatment of inflammation and pneumococcal pneumonia-induced sepsis

MRNA-046 Marina Liposome; WO20100173 DiLA2 liposome-fommlated siRNA (Unlocked

Biotech Oligonucleotide; 1 1 Nucleobase Analog (UNA)-modified siRNA;

Parenteral UsiRNA) that targets birc 5 to prevent survivin expression, for the potential treatment of cancer, including liver cancer (hepatocellular carcinoma)

siRNA AIMP2- Neomics Co Oligonucleotide siRNA agent targeted to AIMP2-DX2, a

DX2 inhibitor Ltd spliced tumorigenic variant of aminoacyl- tRNA synthetase interacting multifunctional protein 2 (AIMP2), lacking exon 2, for the potential treatment of lung cancer

BP-100-1.02 MD Anderson Liposome; WO09814172 liposome -delivered Bel -2 antisense drug, for

Cancer Center Oligonucleotide the potential treatment of lymphoma ending Bio-Path antisense; follicular lymphoma and solid tumors Holdings Parenteral including colon, thyroid and head and neck cancers

KHK-1 Dicerna Oligonucleotide WO20100332 DsiRNA formulated using Dicerna' s

Pharmaceutic 25 proprietary Dicer Substrate Technology and als Kyowa Kyowa's proprietary delivery system, which Hakko Kirin target K-ras, for the potential treatment of cancers including hepatocellular carcinoma

EZN-4150 Roche Oligonucleotide WO20090710 Locked Nucleic Acid (LNA)-based antisense

Innovation antisense 82 oligonucleotide targeting the phosplioinositide

Center 3 -kinase gene (PIK3CA) for the potential

Copenhagen treatment of cancer

A/S

RG-012 Regulus Oligonucleotide WO201 1 1268 single-stranded, chemically modified, antisense

Therapeutics antisense; 42 oligonucleotide that inhibits microRNA-21 (a

Subcutaneous downregulator of protein sprouty homolog 1 expression), for the potential subcutaneous treatment of fibrosis, hepatocellular carcinoma (ITCC), and Alport Syndrome

EDN-OL1 St Louis Oligonucleotide WO20091055 antisense oligonucleotide targeting amyloid

University antisense; 72 beta protein production, for the potential

Parenteral treatment of Alzheimers disease (AD) and

Down syndrome RecQ-siRNA Alnyiam Oligonucleotide RecQLl helicase inhibitor, RecQ-siRNA, Pharmaceutic delivered using Nippon Shinyaku's drug ais GCR1 delivery system, for the potential treatment of cancer, especially liver tumors

Atu-11 1 Silence Lipid; siRNA Aiigiopoietin-2 inhibitor, administered

Therapeutics Oligonucleotide; using the DACC-siRNA delivery system, for pic Parenteral the potential treatment of acute lung injury and sepsis

oliqonucleotide Idera. Oligonucleotide; WO20090184 toll like receptor agonist, immunoduiatory toll like receptor Pharmaceutic Parenteral 31 oligonucleotides (IMOs), specific for receptors aqonists als 7, 8 or 9, as adjuvants for the potential

incorporation into Merck & Go's therapeutic and prophylactic vaccines

DIMS-9054 InDex Oligonucleotide WO2()i()0534 DNA-based immunomodulatory sequence that

Pharmaceutic 35 stimulates TLR9 and enhances the production ais AB of IFN-beta, for the potential treatment of steroid resistant pulmonary inflammation siRNA-EphA2- MD Anderson Liposome; liposomal EphA2 siRNA (siRNA-EpliA2- DOPC Cancer Center Oligonucleotide; DOPC), for the potential treatment of cancers,

Parenteral including pancreatic ductal adenocarcinoma

(PDAC) and ovarian cancer

RAS-001 Memorial Oligonucleotide antisense oligonucleotide inhibitor of Ras- 1

Sloan- antisense; ( sr-1) gene expression, for the potential ettering Parenteral treatment of cancer, including pancreatic and Cancer Center lung cancers

Ras

Therapeutics

MIRNA-Rx07 Yale Lipid; M1RNA-Rx07, which mimics endogenous let-

University Oligonucleotide 7 microRNA (miR-Rx-let-7), for the potential Mima antisense; treatment of cancer including NSCLC and

Therapeutics Parenteral prostate cancer

(Asuragen)

STP-900 Sirnaomics Nanoparticle; nanoparticle of multi -targeted siRNA

Oligonucleotide; therapeutic cocktail, for the potential treatment

Parenteral of complications following organ

transplantation

STP-503 Simaomics Nanoparticle; nanoparticle of multi -targeted injectable

(Trisi!ensa) Oligonucleotide; siRNA therapeutic combination that targets

Parenteral EGFR, Raf-1 and mammalian target of

rapamycin genes, for the potential treatment of solid tumors, including breast cancer

STP-705 Sirnaomics Dermatological; WO00147496 siRNA-inhibiting polymeric nanoparticles,

(Cutasil, ketelani) Guangzhou Nanoparticle; consisting of siRNA duplexes targeting genes

Xiangxue Oligonucleotide (TGF-betal, and Cox2) involved in scar

Pharmaceutic formation, along with the polymer delivery al carrier (HKP), in a dermatological cream for the potential prevention and treatment of wounds during the skin's healing process

STP-702 Sirnaomics Aerosol inhalant; multi-targeted aerosol of siRNA therapeutic

(Sirflunib; Inhalant; that targets the IT5N1 and H1N1 strains of FiuQuit) Oligonucleotide influenza, in the lung, for the potential

intranasal treatment of influenza, virus infection antisense Isis Oligonucleotide WO20110320 antisense oligonucleotides (ASOs) targeting oliqonucleotides Pharmaceutic antisense 45 huntingtin expression, including ISIS-388241, ais ISIS-387898 and ISIS-408737, for the potential treatment of Huntington's disease (HD) TKM-Marburq Protiva Liposome; siRNAs using its LNP technology (formerly Biotherapeuti Nanoparticle; stabilized nucleic acid lipid particles (SNALP) cs Oligonucleotide; delivery system), as TKM-Marburg (presumed

Parenteral to be Pro-MARV), which target an imdisclosed filovirus gene, for the potential treatment of Marburg virus infection

ATL-1 102 (ISIS- Isis Inhalant; WO00020635 second-generation antisense nucleotide

107248) Pharmaceutic Oligonucleotide targeting CD49d (VLA-4) mRNA, for the als / Antisense antisense potential treatment of asthma Therapeutics

(ANP),

antisense Ben-Gurion Oligonucleotide WO20051019 antisense therapy, which inhibits cytosolic therapy University Of antisense 68 phospholipase A2 (cPLA2) formation, for the

The Negev potential treatment of amyotrophic lateral sclerosis and inflammation including rheumatoid arthritis

antisense Isis Oligonucleotide WO20050139 antisense oligonucleotides which inhibit miR- oliqonucleotides Pharmaceutic a tisense; 01 122, a liver-specific microRNA (miRNA) als / Regulus Parenteral involved in cholesterol metabolism and

Therapeutics, hepatitis C virus (HCV) replication, for the GSK potential treatment of HCV infection and associated steatosis

ALN-HBV Sirna Intravenous; WO03070918 RNAi therapeutics, targeting the HBV genome,

Therapeutics Oligonucleotide; developed using Enhanced Stabilization

Subcutaneous Chemistry - GalNAc-conjugate technology for the potential sc treatment of hepatitis B virus (HBV) infection

IM02125 Idera I tratumorai; WO20050010 TLR-9 agonist IMO-2125 (previously HYB-

Pharmaceutic Oligonucleotide; 55 2125), an interferon-alpha and -gamma als Subcutaneous production inducing immunomodulatory oligonucleotide that increases Thl cytokine production, for the potential

intratumorai treatment of cancer

Factor 5A1 Sevion Oligonucleotide; WO20060147 eI.F-5Ai (Factor 5A1 ) gene-silencing si RNA qene-silencinq Therapeutics Parenteral 52 for the potential treatment of inflammation siRNA

hairpin RNA SomaGenics Lipid; WO20100453 small hairpin RNAs (shRNAs) targeting the IRES inhibitors Nanoparticle; 84 hepatitis C vims (HCV) internal ribosome

Oligonucleotide entry site (IRES) for the potential treatment of

HCV infection

RX-0047N (RX- Rexahn Liposome; WO20040669 nanoliposomal antisense oligonucleotide 0047-Nano;RX- Pharmaceutic Nanoparticle; 49 hypoxia inducible factor- 1 alpha (HIF- 1 alpha)

0047) als Oligonucleotide inhibitor, for the potential treatment of cancers, antisense; including lung, prostate and breast tumor

Parenteral

AE-298p Antigen Intratumorai; WO20081 122 intratumorai antisense oligonucleotide that

Express Oligonucleotide 18 targets li (MHC class Il-associated invariant antisense chain) mRNA for the potential treatment of

HIV infection

bevasiranib Acuity Local; WO20040097 a. targeted siRNA against the VEGF-encoding

(Cand5), Pharmaceutic Oligonucleotide; 69 gene converted into self delivering (sd)- als Ophthalmic rxRNA, for the potential treatment of

exudative age-related macular degeneration (wet AMD)

OGX-225 OncoGenex Oligonucleotide WO03030826 antisense inhibitors of insulin-like growth

Technologies antisense; factor binding proteins (IGFBPs), which

Parenteral inhibits IGFBP-2 and IGFBP-5, for the potential treatment of solid tumors including glioma, bladder, breast cancer and prostate tumor

ISIS-DGAT2RX Isis Oligonucleotide diacylglycerol acyltransferase (DGAT)

Pharmaceutic antisense; antisense oligonucleotides (ASO), including als Parenteral ISIS-DGAT2RX, for the potential treatment of non-alcoholic steatohepatitis (NASH), and metabolic disorders including type 2

ATL-1 101 Antisense Oligonucleotide; WO20040722 second generation antisense oligonucleotide

Therapeutics Parenteral; 84 targeting insulin-like growth factor- 1 receptor

Ltd Subcutaneous (IGF-IR) mRNA for the potential sc treatment of prostate cancer

SB-40 (ORI- OriGenix Nucleotide and WO09639502 nucleotide inhibitors of hepatitis B v ims

9020) oral Technologies derivatives; (ITBV) replication for the potential treatment of prodrug SB-44 / Spring Bank Oligonucleotide; WO20120306 HBV infection

Oral; Prodrug 26

NOX-L41 NOXXON Small molecule WO03093472 calcitonin gene related peptide (CGRP)

Pharma. AG therapeutic; antagonists (spiegelmer) including NOX-C89,

Spiegelmer NOX-732045 and NO -732096, for the potential treatment of chronic pain, including migraine

aqatolimod (PF- Coley Intratumoral; WO09818810 short strand toll-like receptor-9 (TLR-9)

35 12676, Pharmaceutic Intravenous; agonist immunostimulatory oligonucleotides Pro une; al Group Oligonucleotide; containing un methylated CpG motifs, as a Vaximmune, Subcutaneous vaccine adjuvant for the potential treatment or CpG-7909, PF- prophylaxis or treatment of infectious disease

676) and cancer

Oraqens Temple Oligonucleotide; WO09608256 single-stranded RNA based oral products,

University Oral WO09856384 referred to as Oragen compounds, for the

Hemispherx WO09856385 potential treatment of various viral infections, including HIV and ITBV

IQP-0831 (ISIS- Isis Dermatoiogical; WO091 18004 antiviral ph o sph orothioate oligonucleotide of

5320) Pharmaceutic Intravenous; sequence TTGGGGTT which binds to HIV als / ImQuest Oligonucleotide; receptor gpl20, as a. topical microbicide for the

Vaginal potential prevention of sexual transmission of

HIV infection

ALN-RSV02 Alnylam Oligonucleotide WO20100485 siRNA agents that target the respiratory

Pharmaceutic 90 syncytial virus (RSV) N gene and inhibit viral als / Kyowa replication, for the potential treatment or Hakko Kirin prevention of RSV infection

AVI-7537 Sarepta Oligonucleotide WO20060504 single oligomer component of AVI-6002), a

Therapeutics antisense; 14 Neugene antisense translation suppressing

Parenteral; oligomer (TSO) targeting the Ebola, essential Systemic protein VP24 for the potential prevention and treatment of Ebola virus infection

IPH-3201 Cancer Oligonucleotide single-stranded RNA toll-like receptor-7, -8

Research (TLR7), (TLR8) modulators, IPH-32XX, for Technology the potential treatment of cancer and as a Ltd Innate vaccine adjuvant

Pharma

VEGF-silencinq Alnylam Oligonucleotide WO20050892 antiangiogenic vascular endothelial growth siRNAs, Pharmaceutic 24 factor (VEGF) gene-silencing chemically-

Alnvlam als / Merck & modified siRNAs, including ALN-VEGOl , for

Co the potential treatment of ocular diseases, including age-related macular degeneration (AMD) and diabetic retinopathy LOR-2040 (GTI- Aptose Intravenous; WO09805769 phosphorothioate antisense oligonucleotide 2040) Biosciences Intravesical; which targets R2 ribonucleotide reductase

(Loras, Oligonucleotide mRNA, for the potential iv treatnient of cancer,

National antisense including superficial bladder cancer

Cancer

Institute

(NCI))

GT-1 106 Gen set SA Oligonucleotide oligonucleotide under development for the ex- vivo treatment of chronic myelogenous leukemia by bone marrow purging abetimus (I.J - La Jolla Antigen; WO091 10426 oligonucleotide conjugate, for the potential 394, Riquent) Pharmaceutic Oligonucleotide treatment of renal disease associated with lupus al Co / conjugated WO09213558 erythematosus

BioMarin

Pharmaceutic WO09507073

als

GT-3021 Genset SA Oligonucleotide GT-3021 is a. dumbbell shaped, double

stranded, phosphodiester sense oligonucleotide (decoy) which binds to ICP4, the major viral transactivator, thereby blocking its role in replication of Herpes simplex type-I oliqonucleotides Gen set SA Oligonucleotide oligonucleotides for potential use in the

treatment of viral infections

microRNA-145 Glasgow Oligonucleotide; WO20141518 micro RNA- 145 (miR-145) inhibitor for the inhibitor University Parenteral 35 potential treatnient of pulmonary arterial miRagen hypertension (PAH)

Therapeutics

EDN-OL202 St Louis Oligonucleotide WO00142266 an antisense oligonucleotide, for the potential

University / antisense; treatnient of stroke and traumatic brain injury Edunn Parenteral

Biotechnolog

y

ALN-APC Alnylam Nanoparticle systemic protein C targeting RNAi therapeutic,

Pharmaceutic injectable; for the potential treatment of hemophilia als Oligonucleotide;

Subcutaneous

EXC-005 Isis Local; antisense oligonucleotide (ASO), which targets

Pharmaceutic Oligonucleotide genes that regulate fibrosis and scarring for the als antisense potential local treatment of fibrosis

EXC-004 Isis Local; antisense oligonucleotide (ASO), which targets

Pharmaceutic Oligonucleotide genes that regulate fibrosis and scarring for the als antisense potential local treatment of fibrosis

EXC-003 Isis Local; antisense oligonucleotide (ASO), which targets

Pharmaceutic Oligonucleotide genes that regulate fibrosis and scarring, from als antisense its antisense program, for the potential local treatment of fibrosis

EXC-002 Isis Local; antisense oligonucleotide (ASO), which targets

Pharmaceutic Oligonucleotide genes that regulate fibrosis and scarring for the als antisense potential local treatment of fibrosis siRNA University of Nanoparticle glucose encapsulated siRNA therapeutics, therapeutics Massachusetts oral; targeted to TNF -alpha or MAP4K4 production,

Medical Oligonucleotide; for the potential oral treatment inflammatory School Galena Oral disorders, including rheumatoid arthritis (RA) Biopharma

TKM-HCC Alnylam Liposome; siRNA therapy targeting both Wee! and CSN5

Pharmaceutic Nanoparticle (combinatorial siRNA therapy), delivered als / Tekmira. injectable; using the company's lipid nanoparticle (LNP) Pharmaceutic Oligonucleotide technology for the potential treatment of als cancer, including hepatocellular carcinoma

XDR-TB Sarepta Oligonucleotide RNA-based therapeutics, synthesized using

Therapeutics antisense; AVI's PMO technology platform, for the

Parenteral potential treatment of extensively drug- resistant Mycobacterium tuberculosis infection (XDR-TB)

XEN-701 Isis Oligonucleotide antisense inhibitors of hemojuvelin and/or

Pharmaceutic antisense; hepcidin mRNA, for the potential treatment of als / Xenon Parenteral anemia, of chronic disorders (ACD) or anemia, Pharmaceutic of inflammation (A I)

als

Leukozene ZaBeCor Oligonucleotide; siRNA targeting spleen tyrosine kinase (Syk),

Pharmaceutic Parenteral for the potential treatment of chronic al Co / lymphocytic leukemia

Biothorpe

Lvmphozene ZaBeCor Oligonucleotide; siRNA targeting spleen tyrosine kinase, for the

Pharmaceutic Parenteral potential treatment of B-cell lymphoma al Co /

Biothorpe

Rebelex ZaBeCor Oligonucleotide; siRNA targeting spleen tyrosine kinase (Syk),

Pharmaceutic Parenteral for the potential treatment of acute al Co / myelogenous leukemia

Biothorpe

anti-miR-33 Regulus Oligonucleotide anti-miR-33 antisense oligonucleotides, antisense Therapeutics antisense; including those targeting miR-33a and miR- oliqonucleotide Systemic 33b, for the potential treatment of

cardiovascular and metabolic diseases (including atherosclerosis and metabolic syndrome)

ATL-1 101 Antisense Dermatological; antisense oligonucleotide targeting insulin-like

Therapeutics Emulsion; growth factor- 1 receptor (TGF-1 R) mRNA for

Ltd Oligonucleotide the potential treatment of psoriasis

antisense

radavirsen Sarepta Intravenous; US- antisense inhibitor, incorporating the (AVI-7100, AVI- Therapeutics Oligonucleotide 07943762; company's PMOplus chemistry technology, for

7367) antisense US- the potential treatment of HIN 1 influenza virus

08785407; infection

WO20070305

76;

WO20070306

91 ;

WO20070564

66

GEN-037 Genesis Oligonucleotide ssRNAi technology (complimentary RNA

Research and oligonucleotides delivered separately that Development anneal within the target cell to provide specific Corp Ltd gene silencing) against the target GEN-037 for the potential treatment of solid tumors

GEN-071 Genesis Oligonucleotide RNAi therapeutics against the target GEN-071 ,

Research and a. transcription factor linked to breast cancer Development and other tumor types, for the potential Corp Ltd treatment of solid tumors

GEN-037 Genesis Oligonucleotide RNAi therapeutics against the target GEN-037,

Research and an enzyme involved in nucleotide metabolism, Development for the potential treatment of solid tumors Corp Ltd

GEN-a12 Genesis Oligonucleotide RNAi therapeutics against the target GEN-al2,

Research and a. receptor overexpressed in prostate tumor Development cells, for the potential treatment of prostate Corp Ltd cancer

Atu-134 Silence Liposome; an ti -angiogenic siRNA agent targeting CD31 ,

Therapeutics Oligonucleotide; based on its AtuPlex liposomal delivery pic Parenteral technology, for the potential treatment of solid tumors

REG-3 Archemix Drug WO20101417 dual platelet activator and platelet glycoprotein

Corp / Regado combination; 71 VI inhibitor aptamer, RB-571, and a matched Biosciences Oligonucleotide active control agent, RB-515, for potential iv treatment of vascular diseases including diabetic vascular disorders and as antiplatelet therapy in patients with acute coronary syndrome

AVI-5038 Sarepta Oligonucleotide second-generation pho sphorodiami date

Therapeutics antisense; morpholino oligomer (PMO)-peptide conjugate

Parenteral; Protein (PPMO), targeted to skip dystrophin gene exon conjugated 50, for the potential treatment of Duchenne muscular dystrophy (DMD)

AGX-1053 (Idl - Memorial Oligonucleotide us- AGX-1053 an enantiomer of AGX-51 and a

PCAO) Sloan- antisense; 20150087599; peptide-conjugated antisense oligonucleotide

Kettering Parenteral; WO20090891 that downregulates Id 1 , for the potential Cancer Center Peptide 86 treatment of cancer

AngioGenex

OCM-8055 OncoMune Oligonucleotide; apoptosis-inducing siRNA therapeutic, for the

LLC Parenteral; RNA potential treatment of glioma

technology

OCM-8054 OncoMune Oligonucleotide; WO20090358 BORIS-targeting siRNA, OCM-8054, which

LLC Parenteral; RNA 04 suppresses BORIS expression and causes technology apoptosis, for the potential treatment of breast cancer

Nova-21048 TOPIGEM Drug cationic Novasorb emulsion ophthalmic of

Pharmaceutic combination; TOPIGEN's ASM-8 combination of two Reals / Novagali Emulsion; targeting antisense oligonucleotides, TOP004,

Oligonucleotide which is targeted to b-subunit of IL-3, IL-5 and antisense; GM-CSF receptors, and TOP005, which is

Ophthalmic targeted to CCR3, for the potential treatnient of chronic and seasonal allergic conjunctivitis

NFKappaB A Ges MG Aerosol; WO02066070 NFkappaB decoy oligonucleotide program for decov Inhalant; the potential treatment of respiratoiy tract oliqonucleotides Oligonucleotide inflammation such as asthma, and COPD

MP-42 AnGes MG Injectable; injectable lead from a series of 20-mer double-

Meyer Oligonucleotide; stranded DNA NFkappaB decoy

Pharmaceutic Parenteral oligonucleotides for the potential treatment of als rheumatoid arthritis (RA)

STP-601 Simaomics Nanoparticle; us- nanoparticle of a. combination of three siRNA s

(Acurita) Guangdong Oligonucleotide; 20130123330 that target VEGF, VEGFR1 and VEGFR2,

Zhongsheng Ophthalmic administered intra vitreously, as an

Pharmaceutic angiogenesis inhibitor for the potential al treatment of ocular neovascu larisation

disorders including age-related macular degeneration, proliferative diabetic retinopathy and herpetic stromal keratitis

microRNA- Rosetta Oligonucleotide WO20051 1 12 antisense oligonucleotide inhibitors of tarqetinq Genomics antisense 1 1 ; microRNAs (including miR-191) for the antisense Ltd, Reguius WO20071482 potential treatment of liver cancer oliqonucleotide Therapeutics 35

therapy

NU-172 Archemix Intravenous; aptamer that inhibits thrombin (Factor Ila), for

Coip ARCA Oligonucleotide the potential iv (bolus and infusion) treatment biopharma of thrombosis which could occur during coronary artery bypass graft (CABG) surgery

CTi-1 Silence Inhalant; chemically stabilized modified siRNA therapy

Therapeutics Oligonucleotide designed to inhibit Quark's proprietary target AG Quark RTP801 (part of the HIF-1 pathway), for the Biotech (QBI) potential treatment of chronic obstructive pulmonary disease (COPD)

FFC-15 Faustus Injectable; antisense oligonucleotides against Ki-67

Forschiings Intravesical; antigen, for the potential treatment of solid

Cie Local; tumors such as bladder and renal cancer

Trans lational Oligonucleotide

Cancer antisense;

Research Parenteral

GmbH

ALN-FLU01 A!nylam Oligonucleotide siRNA that targets the NP and PA genes of the

Pharmaceutic influenza, vims and inhibits viral replication, als / Novartis for the potential treatment and prevention of influenza, including the II5N1 avian strain

MDR-03030 Galenea Corp Inhalant; Lipid; WO20040284 intranasal Dicer substrate siRNA candidates

Marina Nasal; 71 which acts against the PB2 gene and are paired

Biotech Oligonucleotide with MDRNA's DiLA2 lipid-based platorm, for the potential prevention and treatment of infleunza virus infection

AVI-7288 Sarepta Infusion; WO20060504 single oligomer component of AVI-6003, a

Therapeutics Intravenous; 14 NeuGene antisense translation suppressing

Oligonucleotide oligomer (TSO) targeting the Marburg virus antisense essential protein VP24, created using the company's PMOplus technology, for the potential iv treatment and/or prevention of Marburg virus infection

eqaptivon peqol Archemix Infusion; WO20050868 a PEGylated aptamer that targets the Al

Corp Intravenous; 35; domain of von WiUebrand factor (vWF) for the

Oligonucleotide; WO20060338 potential treatment of thrombocytopenia in PEGylated 54 patients with type 2b Von WiUebrand disease

TKM-ApoB Alnylam Intravenous; WO20060369 short interfering R A ( siRNA s) that silences

(ApoB SNAL; Pharmaceutic Liposome; 16 the gene for apolipoprotein B (apoB), created PRO-040201) als / Tekmira Nanoparticle using the company's lipid nanoparticle (LNP)

Pharmaceutic injectable; delivery technology (previously known as als Oligonucleotide stabilized nucleic acid lipid particles (SNALP) delivery system), for the potential iv treatment of hypercholesterolemia

alicaforsen Isis Intravenous; WO09960012 RNa.se H-dependent antisense inhibitor of

(intravenous) Pharmaceutic Oligonucleotide intercellular adhesion molecule (ICAM)-l , for

(ISIS-2302) als antisense the potential treatment of Crohn's disease

(CD), rheumatoid arthritis (RA) and kidney transplant rejection

CD40 mRNA- Isis Liposome; WO20060483 CD40 antisense oligonucleotides (ASOs), tarqetinq Pharmaceutic Oligonucleotide 29 including Nov-038, formulated in charge- antisense als / Novo so m antisense reversible liposomes (Smarticles, nov-051 ) for oliqonucleotides AG intracellular delivery, targeting CD40 niRNA for the potential treatment of inflammatory diseases (such as Crohn's disease, organ transplant or rheumatoid arthritis (RA)) and B- cell malignancies

QAX-935 (IMO- Idera Oligonucleotide; WO20100883 immunomodulatory oligonucleotide (IMO)

2134) Pharmaceutic Parenteral; 95 candidates, including H YB-2093, that act als Systemic through TLR-9 to downregulate Th2 immune responses including immunoglobulin E production, for the potential treatment of asthma and allergy

AIR-645 (ISIS- Isis Aerosol inhalant; WO20060918 second-generation, i haled aerosol of an anti-

369645) Pharmaceutic Inhalant; 41 IL-4 receptor-alpha antisense dual inhibitor of als / A 1 taii- Oligonucleotide IL-4 and IL-13, for the potential weekly- Therapeutics antisense treatment of asthma, rhinitis and other lung diseases

antisense Isis Oligonucleotide WO09915648 antisense inhibitor of thymidylate synthase, for oliqonucleotides Pharmaceutic antisense the potential treatment of cancer oligo 83 als / Sarissa

AVI-5126 Sarepta Intravenous; WO20040970 NeuGene antisense compound targeting c-myc

(Resten-CP) Therapeutics Oligonucleotide 17 that incorporates the company's proprietary antisense; Protein drug deliveiy peptide CytoPorter conjugated to conjugated antisense AVI-4126, for the potential treatment of restenosis following coronary artery bypass graft (CABG)

Avrina Anesiva Dermatological; WO20050560 dermatological of NF-kappa-B Decoy, an

Transcription Oligonucleotide 20 oligonucleotide that binds to the transcription

Factor factor nuclear factor-kappa-B, for the potential

Therapeutics treatment of inflammatory disorders including

(TFT) eczema, rheumatoid arthritis and asthma

ISIS-EIF4ERX Isis Infusion; WO20050286 second-generation antisense drag candidate

(ISIS-183750; Pharmaceutic Intravenous; 28 that targets eukaryotic initiation factor-4E (elF- e!F-4E ASO, LY- als Oligonucleotide 4E) mRNA, for the potential iv -infusion 2275796) antisense treatment of cancer

AG N-21 1745 Sima Injectable; WO03070918 (AGN-745, formerly Sirna-027), an intravitreal

Therapeutics Oligonucleotide; injectable small interfering RNA (siRNA) that Ailergan Ophthalmic; WO03072590 targets VEGFR-1 mRNA, for the potential

Parenteral treatment of age-related macular- degeneration

WO20041 112 (AMD)

37

NOX-B11 NOXXON Intravenous; WO20040132 spiegelmer-based ghrelin inhibitor, for the

Pharma. AG Spiegelmer 74; potential treatment of obesity

WO20050498

28

ARC- 183 Archemix Oligonucleotide anti-thrombin aptamer with a short half-life, as

Corp Nuvelo a potential anticoagu!ant anti thrombotic to prevent clotting during artery bypass graft (CABG) surgery

AEG-35156 Idera Infusion; WO00226968 19-mer phosphorothioate antisense

Pharmaceutic Intravenous; oligonucleotide targeting the caspa.se inhibitor als / Aegera Oligonucleotide X-linked inhibitor of apoptosis protein (XIAP) antisense mRNA, for the potential treatment of cancer

ISIS-353512 Isis Infusion; WO20090618 antisense oligonucleotides that inhibits C- (ISIS-CRPRx; Pharmaceutic Intravenous; 41 reactive protein (CRP), for the potential iv ISIS-329993) als Oligonucleotide treatment of cardiovascular and inflammatory antisense diseases such atrial fibrillation (AF)

AVE-0675 Coley Inhalant; WO00222809 DNA oligonucleotides containing CpG motifs,

Pharmaceutic Oligonucleotide as a toll-like receptor 9 (TLR-9) agonist for the al Group / potential inhalational treatment of asthma. Sanofi-aventis

qataparsen (LY- Isis Infusion; WO00018781 second-generation antisense oligonucleotide

2181308, ISIS- Pharmaceutic Intravenous; drug targeting survivin mRNA, for the 23722) als / Eli Lilly Oligonucleotide potential iv infusion treatment of non-small- antisense cell lung cancer (NSCLC), prostate cancer and acute myeloid leukemia. (AML)

ISS vaccine Dynavax Antigen; WO09855495 immunostimulatory sequence ISS- 1018, an

Technologies Oligonucleotide; adjuvant that acts as a TLR-9 agonist, in

Corp Parenteral combination with, or linked to, antigens as a potential treatment for cancer

ISS-based Dynavax Antigen; WO00021556 immunostimulatory DNA sequence (ISS) therapies Technologies Oligonucleotide adjuvant that acts as a. TLR-9 agonist, linked or

Coip WO09816247 combined with HIV antigens, for the potential treatment of HIV infection

WO09855495

locked nucleic Exiqon A/S Injectable; WO00148190 Locked Nucleic Acid (LNA) antisense acid Cureon Oligonucleotide oligonucleotides for the potential treatment of therapeutics antisense; various indications, including cancer,

Parenteral neurodegenerative diseases and allergies rev-RRE NascaCell Oligonucleotide; WO02053731 small molecules, designed to inhibit the inhibitors, GmbH Ribozyme interaction between rev and RRE, for the

NascaCell potential treatment of HIV infection iCo-007 (ISIS- Isis Injectable; WO20040031 intravitreally delivered antisense

13650) Pharmaceutic Oligonucleotide 34 oligonucleotide inhibitor of c-raf kinase (Rail ), als antisense; for the potential treatment of age-related

Ophthalmic; macular degeneration (AMD) and diabetic

Parenteral retinopathy including diabetic macular edema

(DME)

Huntinqtons Tapestry Oligonucleotide WO03013437 o!igonucieotide-based therapy for the potential disease therapy Pharmaceutic treatment of Huntington's disease (HD)

als

anti-obesitv Abbott Oligonucleotide WO00157081 agents including ML- 106791, A-13X , ASR-1 aqents, Abbott Laboratories antisense and FATP4 for the potential treatment of obesity and type 2 diabetes

AVI-4065 Sarepta Oligonucleotide WO20090644 NeuGene antisense compound, for the potential

Therapeutics antisense; 71 sc treatment of hepatitis C virus (HCV)

Subcutaneous ^■infection

ISIS-1 13715 Isis Infusion; WO00153528 antisense inhibitor of the PTP-1 B gene which

Pharmaceutic Intravenous; was part of the ISIS-PTPl BRx program, for als Oligonucleotide; the potential iv infusion treatment of type 2

RNA antisense; diabetes

Subcutaneous

AS-3 University of Oligonucleotide VEGF phosphorothioate antisense

California Los antisense oligonucleotide AS-3 for the potential Angeles treatment of pancreatic cancer

peptide- Sarepta Oligonucleotide us- peptide-conjugated phosphorodiami date coniuqated Therapeutics antisense; 07943762; morpholino oligomers (PPMOs), including phosphorodiami Parenteral; US- RX6B-AcpP, RXR4B-AcpP, RFF3RXB-AcpP date morpholino Peptide 08785407; and AcpP-PPMO, for the potential treatment of oliqomers WO20070305 bacterial infections, including Mycobacterium

(antimicrobial), 76; tuberculosis infection

Sarepta WO20070306

therapeutics 91 ;

WO20070564

66 oliqodeoxvnucle University of Oligonucleotide WO09526204 phosphorothioate oligodeoxynucleotides, otides, Colev Iowa Coley including compounds CpG-1826 (ODN-1826)

Pharmaceutic WO09602555 and CpG-2216 (ODN-2216) and CpG-2395, as al Group therapeutics and adjuvants, for the potential treatment of cancer, including acute myelogenous leukemia (AML) and melanoma, and infectious diseases

MG-98 MethylGene Infusion; WO09940186 second-generation antisense oligonucleotide

Intravenous; which inhibits expression of the DNA Oligonucleotide niethyltransferase-1 (DNMT-1) gene, for the anti sense potential iv infusion treatment of cancer

ISIS-104838 Isis Dermato logical; WO00020645 antisense oligonucleotide targeting TNF -alpha,

Pharmaceutic Injectable; for the potential treatment of inflammatory a Is Oligonucleotide diseases such as rheumatoid arthritis (RA), anti sense; Crohn's disease and psoriasis

AVI-4126 Sarepta Intravenous; WO00045167 antisense oligonucleotide targeted to the c-myc

Therapeutics Microparticle; niRNA, for the potential treatment of

Oligonucleotide restenosis (as Resten-NG delivered via antisense catheter, and as Resten-MP delivered iv using microbubble technology')

aprinocarsen [sis Intravenous; WO09960012 antisense phosphorothioate oligonucleotide

(LY-900003; Pharmaceutic Oligonucleotide PKC-aipha expression -inhibitor, for the

ISIS-3521) als antisense potential treatment of solid tumors that are refractory to, or recurrent with, standard treatment regimens

oblimersen Genta Infusion; WO09508350 antisense oligonucleotide complementary to

(Genasense; G- Intravenous; bcl-2, as an iv drip infusion for the potential

3139) Oligonucleotide treatment of various cancers, including chronic antisense lymphocytic leukemia (CLL) and non-small- cell lung cancer (NSCLC)

miR-208 miRagen Oligonucleotide single-stranded antisense oligonucleotide, inhibitors Therapeutics antisense; using Santaris Pharma 's Locked Nucleic Acid

Parenteral (LNA) Drag Platform, for the potential treatment of obesity and cardiometaboiic disorders

Atu-664 Silence Lipid; siRNA that targets transthyretin (TTR), using

Therapeutics Oligonucleotide the lipid-based DBTC-siRNA delivery system, pic for the potential treatment of TTR-amyloidosis

Atu-047 Silence Lipid; siRNA that lowers the levels of factor VII,

Therapeutics Oligonucleotide delivered using the lipid-based DBTC-siRNA pic deliveiy system, for the potential prevention of thrombosis

Atu-044 Silence Lipid; siRNA that inhibits apolipoprotein B (apoB),

Therapeutics Oligonucleotide; delivered using the lipid-based DBTC-siRNA pic Parenteral delivery system, for the potential treatment of hypercholesterolemia

DCR-0729 Dicerna Oligonucleotide; siRNAs (DsiRNAs) program, formulated using

Pharmaceutic Parenteral Dicerna's proprietary Dicer Substrate als Technology, for the potential treatment of undisclosed indication

siRNA aqent University of Oligonucleotide siRNA agent that down-regulates the COX-2

University of Iowa. expression and prevents the production of Iowa COX-2 protein, for the potential treatment of cancer

PXS-2200 Pharmaxis Ltd Oligonucleotide; oligonucleotide, for the potential treatment of

Parenteral asthma pbi-shRN K-ras Gradalis Oligonucleotide; pbi-shRN K-ras LP (pbi-shRN K-ras Lipoplex) L RNA technology an shRNA agent targeted to K-ras, for the potential treatment of solid tumors, including pancreatic cancer

anti-FGF8 RNA Ribomic Oligonucleotide anti-FGF8 RNA aptamers for the potential aptamers treatment of prostate cancer

microRNA Nippon Oligonucleotide microRNA (miR)-582-5p/3p for the potential (miR)-582- Shinyakii Co treatment of bladder cancer

5p/3p Ltd

mvelin-bindinq Mayo Oligonucleotide DNA aptamers that bind to myelin and aptamers Foundation promote remyelination for the potential

treatment of multiple sclerosis (MS) miRNA-51 1- Istituto Oligonucleotide therapeutics based on the endogenous based Scientifico H microRNA miRNA- 51 1 for the potential therapeutics San Raffaele treatment of solid tumors

DsiRNAs Dicerna Oligonucleotide Dicer-substrate siRNAs targeting human tarqetinq HER3 Pharmaceutic epidermal growth factor receptor 3 (HF.R3) for als the potential treatment of cancer

DsiRNAs Dicerna Oligonucleotide WO20130326 Dicer-substrate siRNAs targeting human tarqetinq HER2 Pharmaceutic 43 epidermal growth factor receptor 2 (HER2) for als the potential treatment of cancer

DsiRNAs- Dicerna Oligonucleotide WO20130326 Dicer-substrate siRNAs (DsiRNAs) that target tarqetinq Pharmaceutic 43 androgen receptor, for the potential treatment androqen als of cancer

receptor

antisense Isis Oligonucleotide antisense oligonucleotides (ASOs) to block the oliqonucleotides Pharmaceutic antisense; c.216G>A cryptic 5' splice site in USHiC, for als Rosalind Parenteral the potential use in the treatment of Ushers Franklin Syndrome

University of

Medicine and

Science/Louis

iana State

University

ASI-002 OliX Oligonucleotide; shorter-duplex siRNA, for the potential

Pharmaceutic Parenteral treatment of age-related macular degeneration als (AMD)

ASI-001 OliX Oligonucleotide; asymmetric shorter-duplex siRNA (asiRNA),

Pharmaceutic Parenteral for the potential treatment of cancer als

DLL4 tarqetinq University Oligonucleotide anti-angiogenesis miRNA s targeting delta-like miRNA proqram College liga.nd-4 protein (DLL4), for the potential

London treatment of cancer

TGF-beta 1 - Bonac Corp Oligonucleotide WO20131800 RNAi agents (nkRNA, PnkRNA) that suppress tarqetinq RNAi 38 TGF-betai for the potential treatment of aqents pulmonary fibrosis and acute lung injury

C2GnT Kanazawa Oligonucleotide; siRNA, which inhibits C2GnT, for the tarqetinq siRNA University Parenteral potential treatment of cancer including bladder cancer

beta-catenin PhaseRx Oligonucleotide; siRNA conjugates, which inhibits beta-catenin, inhibitors Parenteral for the potential treatment of hepatocellular carcinoma

osteopontin Duke Oligonucleotide osteopontin aptamer, for the potential treatment aptamer University of breast cancer

SonoDOX Epitarget AS Nanoparticle; sonosensitive nanoparticle of siRNA, for the Oligonucleotide potential treatment of liver and breast sarcomas

BOT-103 BiOrion Oligonucleotide PDGFR-beta receptor targeted bi -cyclic octa-

Technologies conjugated; pep tides covalently linked to human serum

BV Parenteral; albumin, as targeted siRNA therapy, for the potential treatment of liver fibrosis miRNA-33 Kyoto Oligonucleotide; miRNA-33 therapeutics for the potential therapeutics University Parenteral treatment of cardiovascular disease

ISIS-FVIIRx Isis Oligonucleotide WO20121741 antisense oligonucleotide that targets Factor

Pharmaceutic antisense 54 VII, for the potenticil treatment or prevention of als thrombosis

EGLN siRNA Alnylam Liposome; siRNA targeting eg! n ine homo log (EGLN)

Pharmaceutic Oligonucleotide; prolyl hydroxlase genes to promote als Parenteral erythropoiesis for the potential treatment of anemia

oblimersen Genta Oligonucleotide antisense oligonucleotide complementary to antisense; bcl-2, for the potential treatment of cancer

Subcutaneous

ANS-36 Advance! 1 Oligonucleotide; siRNA for the potenticil treatment of intestinal

Parenteral diseases

TLR-8 inhibitor Dynavax Oligonucleotide; WO20140529 oligonucleotide -based immunoregulatory

Technologies Parenteral 31 sequence, which acts as a TLR-8 inhibitor, for Corp / GSK. the potential treatment of autoimmune and inflammatory diseases

CCR2-tarqetinq Alnylam Nanoparticle; lipid nanoparticle formulated CCR2 -targeting siRNA therapy Pharmaceutic Oligonucleotide siRNA therapy for the potential treatment of als / MGH, inflammatory diseases, cardiovascular MIT diseases, cancer and transplant rejection

DPC-1528 Altor Oligonucleotide WO20050427 antisense drug, for the potential treatment of

Bioscience antisense 41 acne

Corp

FOLIGO 002 Foligo DNA technology; DNA-based antisense drag modified with Isis's

Therapeutics Oligonucleotide proprietary 2'-methoxyethyi (2'MOE)

antisense chemistry and aims to "knock down" a. protein associated with ovarian carcinogenesis, for the potential treatment of ovarian cancer miR-124 + miR- Mirna Drag microRNA (miRNA) therapeutics that mimic

34a/let-7b/let- Therapeutics combination; endogenous miR-124 in combination with

7c/let-7q Oligonucleotide; miR-34a, iet-7b, let-7c or let-7g, for the

Parenteral potential treatment of cancer including liver and prostate cancer

ApoB siRNA Sirna Nanoparticle; WO20120582 siRNAs targeting apo lipoprotein B and therapy Therapeutics Oligonucleotide 10 formulated in lipid nanoparticles (LNP) for the potential treatment of hypercholesterolemia.

CvD1 -siRNA Immune Liposome; cyclin Dl (CyDl )-siRNA, delivered using

Disease Nanoparticle; integrin-targeted stabilized nanoparticles (I- Institute Oligonucleotide tsNP), a nano-sized neutral liposomes that encapsulate siRNAs, for the potential treatment of inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease

Atu-195 Silence Oligonucleotide; siRNA agent, for the potential treatment of

Therapeutics Parenteral solid tumors

pic

MGN-7455 miRagen Oligonucleotide; single-stranded microRNA-therapeutics

Therapeutics Parenteral targeting miR-199 using Santaris Pharma's

Locked Nucleic Acid (LNA) Drug Platform, for the potential treatment of ischemic heart disease

Np1/ApoB Pfizer Liposome; nanolipid siRNA (lip! ) which targets siRNA Nanoparticle; apo lipoprotein B (ApoB) for the potential

Oligonucleotide; treatment of hepatocellular carcinoma (HCC) Parenteral

LNA anti-miR- Roche Oligonucleotide LNA anti-microRNA (miR)-155 for the 155 Innovation anti sense potential treatment of Waldenstrom's

Center macroglobulinemia (WM) and chronic

Copenhagen lymphocytic leukemia (CLL)

A S

EDP-19 Sheba Local; siRNA agents delivered topically using

Medical Oligonucleotide convection-enhanced delivery technology Center invented at Sheba Medical Center, for the BiolineRx's potential treatment of brain cancer

MGN-5804 miRagen Oligonucleotide; mi roRNA therapeutic targeting miR-378, for

Therapeutics Parenteral the potential treatment of obesity and

cardiometabolic disease, including metabolic syndrome

ALN-HPN A!nyiam Infusion; systemic hepcidin-targeting siRNA

Pharmaceutic Intravenous; therapeutics that act via transferrin receptor als Oligonucleotide subtype 2, for the potential iv treatment of anemia.

TGN-208 TransGenex Nanoparticle; siRNA nanoparticle inhibitor of natriuretic

Nanobiotech Oligonucleotide; peptide receptor A (N RA) expression, created

Parenteral using the company's SiPlex technology, for the potential treatment of cancer and immune disorders

RNAi PlasrnaTech Nanoparticle RNAi therapeutics, based on the company's therapeutics Biopharmaceu oral; proprietary CobaCyte (Cobaiamin (vitamin B- ticals Oligonucleotide; 12)) nan o sphere absoiption enhancement

Oral absorption technology, for the potential oral treatment of enhancer; cancer

Factor XII (FXII) Isis Oligonucleotide antisense oligonucleotide (ASO) Factor XII

Pharmaceutic anti sense (FXII) inhibitors for the potential treatment of als blood clotting disorders, including thrombosis

RhoA siRNAs Quark Oligonucleotide; WO20080503 RhoA siRNAs for the potential treatment of

Pharmaceutic Parenteral 29 neiirodegeneration, neuropathic pain and spinal als cord injury

anti-miR-182 Regulus Oligonucleotide antisense oligonucleotides against the

Therapeutics anti sense microRNA miR-182 for the potential treatment of metastatic cancer

miR-34a mimics Regulus Nanoparticle; WO201 10883 mimics of the endogenous microRNA miR-34a

Therapeutics Oligonucleotide 09 delivered using Alnylam's lipid nanoparticles for the potential treatment of liver tumors

MGN-2677 miRagen Oligonucleotide; single-stranded micro RNA-targeted

Therapeutics Parenteral therapeutics, targeting miR-143/miR-l 45, using Locked Nucleic Acid (LNA) for the potential treatment of restenosis

MGN-8107 miRagen Oligonucleotide; microRNA therapeutic targeting miR-206, for

Therapeutics Parenteral the potential treatment of amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD)

MGN-4893 miRagen Oligonucleotide; microRNA therapeutic that inhibits miR-451 ,

Therapeutics Parenteral using Locked Nucleic Acid (LNA) Drug

Platform, for the potential treatment of polycythemia, vera.

survivin- Marina. Drug WO20100657 UsiRNA targeting the birc5 gene to prevent tarqetinq Biotech combination; 56 survivin expression (presumed to be MRNA- UsiRNA + Liposome; 046) and a PLK.1 -targeting UsiRNA, PLK1 -tarqetinq Oligonucleotide; encapsulated in a. single DiLA2 liposomal , for UsiRNA Parenteral the potential treatment of cancer and malignant ascites

PRO-105 Prosensa. Oligonucleotide single-stranded RNA-based antisense

Therapeutics antisense; oligonucleotide which enhances survival motor

BV Parenteral; RNA neuron (SMN) protein production by post- transcriptional modulation of the SMN2 pre- mRNA, for the potential treatment of spinal muscular atrophy

BP-100-2.01 Bio-Path Liposome; WO20061136 liposome-formulated siRNA targeting focal

Holdings Oligonucleotide 79 adhesion kinase 2 (FAK.2; protein tyrosine kinase 2 beta (PTK2b)), for the potential treatment of cancer including colorectal, head and neck, ovarian and thyroid cancers

AP-15012 Isarna Oligonucleotide antisense oligonucleotide, for the potential

Therapeutics antisense treatment of cancer including malignant GmbH melanoma

SYL-040003 Sylentis Sau Oligonucleotide; siRNA targeting carbonic anhydrase IV

Ophthalmic (CAW) mRNA, for the potential treatment of ocular hypertension, a risk factor for primary open-angle glaucoma (POAG)

anti-VEGF165 OP O Health Oligonucleotide; siRNAs against the angiogenic VEGF isoform siRNA Parenteral VEGF165 and for sparing of the

antiangiogenic i so form VEGF 165b, including OPK-HVB-004 and OPK-HVB-010, for the potential treatment of ocular

neovascularization in wet age-related macular degeneration

BC-822 BioCancell Oligonucleotide; WO20070073 siRNA which prevents the expression of H- 19

Therapeutics Parenteral;; 17 gene, for the potential treatment of cancer

Ltd

FXI antisense Isis Oligonucleotide WO20090618 antisense oligonucleotide factor XI inhibitors oliqonucleotides Pharmaceutic antisense 41 (FXI ASO), including ISIS-404071, FXI- AS 1 als and FXI-AS2, for the potential treatment of thrombosis

FVII antisense Isis Oligonucleotide antisense oligonucleotides that act as Factor oliqonucleotides Pharmaceutic antisense; VII inhibitors (FVII ASO), for the potential (thrombosis), als Parenteral treatment of thrombosis

Isis

Pharmaceutical

s

GS-326 (GS- Gene Signal Oligonucleotide WO03074073 anti -angiogenic antisense oligonucleotide, for

326C) SAS antisense the potential treatment of pancreatic cancer

MDR-09513 Marina Oligonucleotide RNAi technology and delivery system, for the

Biotech potential treatment of lung cancer

MDR-09521 Marina Oligonucleotide RNAi technology and deliveiy systems, for the

(MDRNA- Biotech potential treatment of bladder cancer

ONC1 )

MDR-04227 Marina Lipid; WO20081093 DiLA2 lipid-based formulated Dicer substrate

Biotech Oligonucleotide; 50 siRNA (Unlocked Nucleobase Analog (UNA)- Systemic modified siRNA; UsiRNA) that targets

apolipoprotein B (ApoB), for the potential treatment of hypercholesterolemia.

DsiRNAs Dicerna. Oligonucleotide; WO20130326 DsiRNAs for the potential treatment of

Pharmaceutic Parenteral 43 inflammation, including rheumatoid arthritis als / Kyowa (RA)

Hakko Kirin

CALAA-02 Calando Intravenous; WO20091237 si RNA therapeutic that targets hypoxia

Pharmaceutic Nanoparticle 64 inducible factor-2 alpha. (HIF-2alpha), created als injectable; using the company's RONDEL polymer

Oligonucleotide delivery technology, for the potential treatnient

of cancer, including solid tumors

Atu-150 Silence Oligonucleotide; siRNA agent presumed to target VEGFR2, for

Therapeutics Parenteral the potential treatnient of solid tumors, pic including hepatocellular carcinoma (IICC)

Dqat1/Dqat2 Johnson & Intravenous; Dgat-targeting siRNA duplexes (SNALP- si RNA du lexes Johnson Nanoparticle siDgat) for the potential iv treatment of

Pharmaceutic injectable; hyperlipidemia

al Research & Oligonucleotide

Development

LLC

BXA-9t2 BexCore Co Oligonucleotide; WO20080662 modified, 29 mer, RNA aptamer which inhibits

Ltd Parenteral; RNA 30 hepatitis C vims (HCV) replication, for the technology potential treatment of HCV infection

SPC-3576 Roche Oligonucleotide Sp kl mRNA, a locked nucleic acid (LNA)

Innovation antisense; antisense oligonucleotide, for the potential

Center Parenteral treatment of cancer

Copenhagen

A/S

AVI-3378 Ercole Oligonucleotide antisense therapy based on its Splice Switching

Biotech antisense; Oligonucleotide (SSO) technology, which

Parenteral targets TNF-alpha receptor type 2 (TNFR2),

for the potential treatment of inflammatory disease, including rheumatoid arthritis (RA) and hepatitis

MIRNA-Rx05 Asuragen Oligonucleotide WO20100567 microRNA (miRNA) therapeutic that mimics

37 endogenous miRNA, MIRNA-Rx05 (miR- Rx05 mimetic), for the potential treatment of cancer, including acute myeloid leukemia and prostate cancer

prothrombin Isis Oligonucleotide WO20090 18 second-generation antisense oligonucleotides inhibitors Pharmaceutic antisense 41 (ASOs) that inhibit prothrombin (coagulation als factor Ha, or Flla), including ISIS-401025, for the potential treatment of thrombosis

LOR-1284 Aptose Oligonucleotide WO20060179 siRNA candidate that silences the expression

Biosciences 32 of the R2 subunit of ribonucleotide reductase,

Lorus for the potential treatment of cancer

Therapeutics

ALN-HTT Ainylam Drag implant; WO20061219 siRNA therapy delivered via an implantable

Pharmaceutic Oligonucleotide; 60 pump -infusion system to silence the Huntingtin als Parenteral (htt) gene for the treatment of Huntington's disease (HD)

NaV1 .8 qene- Ainylam Injectable; WO20070563 voltage-gated sodium channel 1.8 (Navl .8) silencinq Pharmaceutic Oligonucleotide; 26 gene silencing small interfering (si)RNAs for siRNAs als Parenteral the potential treatment of chronic pain

CALAA-01 Calando Intravenous; WO20061053 siRNA that suppresses the expression of the

Pharmaceutic Nanoparticle 61 ribonucleotide reductase M2 subunit (RRM2) als injectable; delivered in nanoparticles prepared using the Oligonucleotide company's cyclodextrin-containing RONDEL polymer delivery technology and conjugated to human transferrin to target the drug to cancer cells, for the potential iv treatment of solid tumors

ISIS-199044 Isis Oligonucleotide chimeric oligonucleotide ISIS- 199044, which

Pharmaceutic induces to 11 -like receptors (TLR) 7 and 9, for als the potential treatment of cancer diabetes Sarepta Oligonucleotide antisense -based exon skipping pre-RNA therapy Therapeutics antisense; RNA interference technology (ESPRIT) which antisense expresses CTLA-4, for the potential treatnient

of diabetes

Excellair ZaBeCor Inhalant; WO20050076 once-daily inhaled siRNA agent which targets

Pharmaceutic Oligonucleotide 23 the Syk kinase gene, for the potential al preventive treatment of asthma

ISIS-20408 Isis Oligonucleotide antisense oligonucleotide (ASO) inhibiting

Pharmaceutic antisense Mcl-1 (bcl-2 family protein) for the potential als treatnient of cancer

peqaptanib Eye tech Injectable WO09818480 sustained-release of pegaptanib (Macugen), a controlled release; PEGylated anti-VEGF aptamer with anti- Oligonucleotide; angiogenesis properties, for the potential Ophthalmic; treatment of neo vascular age-related macular PEGylated degeneration

alpha-svnuclein Alnylam Oligonucleotide WO20050047 antisense oligonucleotides (ASOs) and siRNAs qene-silencinq Pharmaceutic antisense 94 to silence aipha-synuclein gene (SNCA) siRNAs als expression, for the potential treatment of

Parkinson's disease (PD)

Raf-1 LE-siRNA NeoPharm Liposome; WO20071008 cardiolipin liposomal (NeoPhectin) siRNA

Oligonucleotide 08 therapy, Raf-1 LE-siRNA, that inhibits the expression of Raf-1 and downregulates cyciin Dl expression, for the potential treatment of cancer

NeuGene Sarepta. Oligonucleotide NeuGene antisense compounds for the antisense Therapeutics antisense; potential treatment of Bacillus anthracis compounds Parenteral infection

AP-1 1014 Isama Oligonucleotide EP02453017 TGF beta i -specific antisense oligonucleotide

Therapeutics antisense AP-1 1014, for the potential treatment of GmbH cancers including non-small-cell lung and prostate cancer

AP-15000 Isama Oligonucleotide antisense oligonucleotide for the potential

Therapeutics antisense treatment of cancer

Atu-012 Silence Oligonucleotide siRNA therapy, for the potential treatment of

Therapeutics age-related macular degeneration (AMD) and

AG cancer

siRNA therapy Genesis Oligonucleotide WO20050804 siRNA therapies for the potential treatment of

Research and 10 allergy

Development

RBL-1 CytoGenix Oligonucleotide antisense oligonucleotide against bacterial antisense DNA-dependent RNA polymerase, for the potential treatment of bacterial infection alicaforsen Isis Dermato logical; WO09960012

Pharmaceutic Oligonucleotide

als antisense

PXSTPI-1 100 TOPIGEN Aerosol inhalant; WO20071344 RNA-targeting oligonucleotide inhibitor of (TPI-PD3; TF'I- Pharmaceutic Oligonucleotide 51 PDE4 and PDE7, for the potential inhalant 1 100; PXS- 1 100) ais antisense treatment of chronic obstructive pulmonary disease (COPD)

ISIS-SGLT2RX Isis Oligonucleotide WO20050380 oligonucleotides targeted to SGLT-2 mRNA,

Pharmaceutic antisense; 13 for the potential sc injection treatment of als Subcutaneous diabetes

NOX-A50 NOXXON Small molecule WO20061 172 spiegelmer high mobility group Al (I IMG- Pharnia AG therapeutic; 17 Alb) inhibitor, from a series of spiegelmer

Spiegelmer transcription factor antagonists, delivered in combination with a polycation , for the potential treatment of cancer

KSR1 antisense Memorial Oligonucleotide phosph orothioate antisense oligonucleotide oliqonucleotide Sloan- antisense (AS-ODN) against kinase suppressor of Ras

Ketteriiig (K.SR1), for the potential treatment of Cancer Center pancreatic cancer

NOX-A42 NOXXON Small molecule spiegelmer-based amylin antagonist, for the

Piiarrna AG therapeutic; potential treatment of diabetes mellitus

Spiegelmer

MDR-06155 Marina Oligonucleotide; WO20070306 siRNA therapy for use with its peptide-based (MDRNA-TNF 1 ) Biotech Parenteral 19 delivery technology, directed against the expression of TNF alpha, for the potential treatment of inflammatory disease, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD)

CY-403 C toGenix Oligonucleotide antisense antibacterial oligonucleotide targeted antisense; against all strains of Staphylococcus aureus,

Parenteral including Methicillin-resistant (MRSA) and

Vancomycin-resistant (VRSA) strains

LNA-based Roche Injectable; Locked Nucleic Acid (LNA) antisense pan-Ras protein Innovation Oligonucleotide oligonucleotides targeting Ras proteins for the mRNA Center antisense; potential treatment of cancer

Copenhagen Parenteral

A/S

beclanorsen Roche Injectable; WO20050617 Locked Nucleic Acid (LNA) antisense

Innovation Oligonucleotide 10 oligonucleotide targeting bcl-2 mRNA, for the

Center antisense; potential treatment of cancer

Copenhagen Parenteral

A S

RNAi therapy Sima Oligonucleotide RNAi -based therapeutics for the potential

Therapeutics treatment of type 2 diabetes Merck & Co

RNAi therapy Sima Local; WO20081377 locally administered, chemically modified,

Therapeutics Nanopaiticle; 76 nanoparticulate systemically delivered short Merck & Co / Oligonucleotide interfering RNAs (siRNAs) for the potential GSK. treatment of asthma

antisense Isis Oligonucleotide WO03053340 antisense oligonucleotide (ASO) connective oliqonucleotides Pharmaceutic antisense tissue growth factor (CTGF) inhibitors for the als potential treatment of chronic kidney disease progression in diabetic nephropathy antisense Isis Inhalant; p38alpha MAP kinase antisense oliqonucleotides Pharmaceutic Oligonucleotide oligonucleotides for the potential treatment of als antisense lung diseases, such as asthma.

ISIS-345794 Isis Oligonucleotide second-generation antisense drug that targets

Pharmaceutic antisense the transcription factor STAT-3, for the als potential treatment of cancer antisense Isis Oligonucleotide WO20051 130 antisense inhibitors of glucose -6 phosphatase oliqonucleotides Pharmaceutic antisense 16 (G6Pa.se) transport protein Tl , for the potential ais treatment of type 2 diabetes antisense Isis Oligonucleotide stearoyl-CoA desaturase-1 (SCD1) antisense oliqonucleotides Pharmaceutic antisense oligonucleotides for the potential treatment of als type 2 diabetes

AVT-06 Avontec Oligonucleotide WO20050491 antiarteriosclerotic compound based on

GmbH 06 Avontec's decoy oligonucleotide technology, for its potential use in the prevention of atherosclerosis

AVT-03 Avontec Oligonucleotide compound synthesized based on Avontec's

GmbH decoy oligonucleotide technology, for the potential treatment of restenosis after angioplasty

AVT-05 Avontec Oligonucleotide anti-inflammatory compound based on

GmbH Avontec's decoy oligonucleotide technology, for the potential treatment of rheumatoid arthritis

AVT-04 Avontec Oligonucleotide anti -inflammatory compound synthesized

GmbH utilizing Avontec's decoy oligonucleotide technology, for its potential use in transplantation

AVT-02 Avontec Dermatological; STAT- 1 -targeting decoy oligodeoxynucleotide

GmbH Oligonucleotide based on Avontec's decoy oligonucleotide technology, as a. topical anti -inflammatory for the potential treatment of psoriasis and dermatitis

AVT-01 Avontec Aerosol; WO03031459 STAT- 1 -targeting phosphorothioate DNA

GmbH Inhalant; duplex oligodeoxynucleotide as inhaled antiOligonucleotide inflammatory for the potential treatment of allergic asthma and other respiratory diseases mutated SOD1 CytRx Corp Oligonucleotide; WO20091024 RNAi therapies against the mutated form of

Galena Parenteral 27 superoxide dismutase-1 (mSODl) for the

Biopharma potential treatment of amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease)

ISIS-SOD1 Rx Isis Infusion; WO03000707 antisense oligonucleotide that suppresses the

(ISIS-33361 1 ) Pharmaceutic Intrathecal; production of superoxide dismutase 1 (SOD1), als Oligonucleotide for the potential intrathecal infusion of

antisense amyotrophic lateral sclerosis (ALS)

ISIS-22783 Isis Oligonucleotide antisense oligonucleotide targeting a splice

Pharmaceutic antisense; junction of Bcl-x, for the potential treatment of als Parenteral cancer

AVI-4126 Sarepta Oligonucleotide antisense oligonucleotide targeted to the c-myc

Therapeutics antisense; Oral mRNA, for the potential treatment of cancer controlled release and cardiovascular restenosis

ARC- 127 Archemix Oligonucleotide WO03106659 anti-PDGF aptamer, for its potential use in

Coip oncology and ophthalmology

CY-301 CytoGenix Dermatological; WO20040522 topically delivered DNA vector, using the

(Simplivir; Oligonucleotide 97 company's synDNA active agent, which is formerly CYGX- antisense targeted to epithelial cells resulting in the 0301) generation of oligodeoxynucleotides for the potential treatment of Herpes simplex virus infection

GTI-2601 Aptose Oligonucleotide antisense compound GTI-2601, which is

Biosciences / antisense complementary to thioredoxin mRNA for the Lorus potential treatment of cancer

GTI-3008 Aptose Oligonucleotide antisense compound for the potential treatment Biosciences / antisense of cancer

Loras

GTI-361 1 Aptose Oligonucleotide antisense compound GTI-361 1 for the potential

Biosciences / antisense treatment of cancer

Loras

GTI-4006 Aptose Oligonucleotide antisense compound, for the potential treatment

Biosciences / antisense of cancer

Loras

EPI-4067 EpiGenesis Oligonucleotide cytokine modulator EPI-4067 for the potential

Pharmaceutic antisense treatment of asthma and allergic rhinitis als

antisense Isis Dermato logical; antisense oligonucleotide inhibitors of the oliqonucleotides Pharmaceutic Oligonucleotide CD80 (B7-1 ) and CD86 (B7-2) genes, in a als antisense topical cream , as a potential treatment for psoriasis

ISIS-15421 Isis Oligonucleotide antisense oligonucleotide focal adhesion kinase

Pharmaceutic antisense (FAK) inhibitor, for the potential treatment of als melanoma

ISIS-1 14926 Isis Oligonucleotide anti-survivin 2'-0-methoxyethyl antisense

Pharmaceutic antisense oligonucleotide, for the potential treatment of als liver tumors

antisense Isis Oligonucleotide WO20090589 2'-0-(methoxy)ethyl (MOE) ribose-modified oliqonucleotides Pharmaceutic antisense 07 antisense oligonucleotides for prostate cancer als and other malignancies

NeuGene Sarepta Oligonucleotide WO00204479 NEUGENE antisense compound, targeting the

Therapeutics antisense TGF-beta gene, as a regulator of bone marrow stem cell proliferation or differentiation for potential use in bone marrow transplantation

GRO-29A University of Oligonucleotide WO03086174 guanosine-rich oligonucleotide (GRO)

Louisville targeting nucleolin, was under development by the University of Louisville for the potential treatment of leukemia

ISIS-22023 Isis Oligonucleotide WO00061 150 Fas-inhibiting antisense oligonucleotide, for

Pharmaceutic antisense the potential treatment of autoimmune forms of als hepatitis

AVI-4014 Sarepta. Oligonucleotide microencapsulated antisense oligonucleotides

Therapeutics antisense (MASO) targeting transcription factor NF- kappaB for the potential treatment of conditions characterized by IL-1 and TNF release, such as septic shock,

glomerulonephritis and acute transplant rejection

ICN-16967 Valeant Oligonucleotide antisense oligonucleotide directed at the CD44

Pharmaceutic antisense gene, for the potential treatment of melanoma als

International

PAN-346 Panacea Oligonucleotide WO00135102 antisense inhibitor of human aspartyl

Pharmaceutic antisense (asparaginyl) beta-hydroxylase (HA AH) which als was being investigated by Panacea for the potential treatment of glioblastoma multiforme

(GBM)

TAG -6 University of Oligonucleotide oligonucleotide which act as a telomere mimic,

Nebraska for the potential treatment of cancer

ISIS-18155 Isis Oligonucleotide VCAM-1 antisense oligonucleotide, for the

Pharmaceutic antisense potential treatment of inflammatory bowel als disease

ISIS-25302 Isis Oligonucleotide TNF alpha, antisense oligonucleotide, for the

Pharmaceutic antisense potential treatment of Crohn's disease (CD) als

ISIS-16609 Isis Oligonucleotide 20-mer antisense oligonucleotides against the

Pharmaceutic antisense (Wilms tumor) WT1 gene , including ISIS- als 16601 and ISIS-16609, for the potential

treatment of tumors such as pediatric kidney tumors and leukemias

ISIS-15999 and Isis Oligonucleotide WO00020635 antisense oligonucleotides targeted against bcl- ISIS- 16009 Pharmaceutic antisense x , for the potential treatment of cancer

als

LOR-2501 Aptose Oligonucleotide WO00047733 antisense oligonucleotide LOR-2501 (GTI-

Biosciences antisense; 2501 ), targeted to the Rl component of

Loras Parenteral WO09805769 ribonucleotide reductase, for the potential

Therapeutics treatment of cancer

antisense Isis Oligonucleotide antisense oligonucleotide inhibitors of ICAM- oliqonucleotides Pharmaceutic antisense 1 , including ISIS-17470, a 2'-0-methoxyethyl als gapmer oligonucleotide derivative of ISIS- 9125, as potential anticancer therapies

ISIS-7597 Isis Oligonucleotide antisense oligonucleotide ISIS-7597 which analoqs Pharmaceutic antisense reverse multidrug resistant protein (MRP)

als associated resistance

ISIS-3466 Isis Oligonucleotide antisense oligonucleotide directed to the pi 20

Pharmaceutic antisense gene with potential application in the treatment als of cancer

ISIS-9125 Isis Oligonucleotide 20-mer phosphorothioate antisense

Pharmaceutic antisense oligonucleotide (PS-oligos) ICAM-1 inhibitor, als for the potential treatment of inflammatory

diseases including inflammatory bowel disease, rheumatoid arthritis, renal and cardiac allograft rejection

ISIS-3082 Isis Oligonucleotide 20-mer antisense phosphorothioate

analoqs Pharmaceutic anti sense oligonucleotide ICAM-1 inhibitor, for the

als potential treatment of inflammation

ISIS-2503 Isis Intravenous; EP00670897; 20-mer antisense oligonucleotide that inhibits

Pharmaceutic Oligonucleotide WO09222651 Ha-ras expression, as a potential treatment for als antisense cancer, particularly gastrointestinal tumors

GEM-231 Idera Intravenous; WO09402498 18-mer hybrid oligonucleotide, for the

Pharmaceutic Oligonucleotide potential iv treatment of cancer als antisense

Experimental

Preparation of PRP

Platelet rich plasma (PRP) for in vitro aggregation testing may be prepared in accordance with Flierl et al, 2015 {supra). Briefly, Blood is collected by venipuncture with a 21-gauge butterfly needle from healthy volunteers into citrate anticoagulant (Monovette; Sarstedt). PRP is isolated by centrifugation at 180g for 10 min. Washed platelets are prepared from PRP by two additional washing centrifugation steps (500g/ 10 min) in the presence of ACD (acid citrate dextrose) buffer, 0.05 μΜ PGEl, and 0.01 U/ml apyrase. The final platelet pallet is resuspended in Tyrode's buffer (137 mmol/liter NaCl, 2.68 mmol/liter KC1, 11 mmol/liter NaHC03, 10 mM Hepes, 0.42 mM NaH2P04 and 5 mM D-Glucose, pH 7.4) in the same volume as the initial PRP and substituted with 1 mM MgC12 and 2 mM CaC12 (final concentration).

In vitro aggregation assay

Platelet aggregation may be suitably determined in an in vitro assay, for example as described in Flierl et al. 2015 {supra). Briefly, PRP is obtained as described above, and platelet- poor plasma (PPP) is prepared by centrifugation of PRP (4000g, 5 min). After 30 min of resting at 37 degr. Celsius, 90 μΐ PRP is added to wells of a 96 well plate, which are prepared with different (concentrations of) oligonucleotides. The plate is then immediately placed in a 96 well reader, and absorbance determined at 595 nm every 30 s for 60 min between vigorous shaking at 37 degr. Celsius. PPP and PRP are used to determine the maximal and minimal aggregation, respectively, as a reference.

The assay described above, is a reliable method to test the effect of counter measures against the activating effect of the oligonucleotide on platelet aggregation, such as the modification of the oligonucleotides as described and claimed herein.

Claims

1. A method for the treatment of an individual in need thereof with an oligonucleotide (ON) to treat or prevent a disease, wherein the ON is capable of causing platelet activation, platelet aggregation and/or thrombus formation at a ON blood plasma concentration of between about 0.01 and 10 μΜ, characterized in that a countermeasure is taken to reduce such platelet activation, aggregation and/or thrombus formation, and/or any side effects thereof.

2. A method according to claim 1 , wherein the oligonucleotide is a phosphorothioated oligonucleotide, preferably a fully phosphorothioated ON.

3. A method according to claim 1 or 2, wherein the countermeasure is selected from the group consisting of (a) choosing the length of the ON to be 17 nucleotides or less; (b) choosing the percentage of phosphorothioate linkages in the ON to be less than 95%, preferably less than 90%, less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35% or 30%; (c) choosing the pattern of phosphorothioation of the ON backbone such that the number of consecutive PS-linkages is 8 or less, preferably 7 or less, 6 or less, 5 or less, 4 or less or 3 or less; (d) administering to the individual, prior to, simultaneously, or after administration of said ON an inhibitor of platelet activation, aggregation or thrombus formation.

4. A method according to claim 1 , wherein said countermeasure comprises the administration to the individual, prior to, simultaneously, or after administration of the ON, an inhibitor of platelet activation, aggregation or thrombus formation, selected from the group consisting of: (i) an inhibitor of collagen (platelet-specific) collagen-receptor interaction, such as antibodies (e.g. anti-GPVI antibody JAQ1) (ii) a COX 1 -inhibitor (e.g. acetylsalicylic acid or a pharmaceutically acceptable salt thereof, or a carbasalate salt); (iii) an inhibitor of the ADP - P2Y12 interaction (iv) an inhibitor of the fibrinogen-GPIIb/IIIa interaction; (v) a NOX- inhibitor, such as NOX1 -inhibitor ML171 , apocynin, or 2-acetylphenothiazine; (vi) an antioxidant, such as vitamin C or diferuloylmethane, or a combination of one or more of (i) to (vi) above.

5. A method according to claim 2, wherein the countermeasure comprises providing an ON with internucleosidic linkages according the general formula ((PS)n-(PO)m)k, wherein n is an integer between 1 and 9 (inclusive) and m is an integer between 1 and 9 (inclusive) and k is an integer between 1 and 50, and wherein the total number of internucleosidic linkages k*(n+m) is between 12 and 100.

6. A method according to any of the previous claims, wherein the individual bears, independently of ON treatment, an increased risk of platelet induced disorders.

7. A method according to claim 6, wherein such individual is genetically predisposed to develop a platelet activation, platelet aggregation or thrombus formation disorder, is predisposed to develop a platelet activation, platelet aggregation or thrombus formation disorder due to life-style or age.

8. A method according to claim 6 or 7, wherein the disorder is selected from deep vein thrombosis, lung embolism, temporary ischemic attack, heart failure, myocardial infarction, stroke, atherosclerosis and vascular dementia.

9. A method according to claim 1 to 8, wherein such treatment comprises chronic use of PS ONs.

10. A method according to any of the previous claims, wherein the treatment comprises administration of the ON through a route selected from the group consisting of intravenous, subcutaneous, intradermal, transcutaneous, intraocular, intravitreal, intramuscular, intracerebral, intra-nasal, oral, rectal or pulmonary administration.

1 1. A method according to any of the previous claims, wherein the mode of administration and/or the presentation of the ON is selected from the group consisting of injection, infusion, inhalation using a nebulizer or spray, topically using a spray, oil or ointment, orally in the form of a powder, liquid, suspension or pill and the like.

12. A method according to any of the preceding claims, wherein the countermeasure comprises the administration of acetyl salicylic acid, or a pharmaceutically acceptable salt thereof.

13. A method according to claim 12, wherein the acetyl salicyl acid, or salt thereof, is administered daily at an oral dose of between 25 - 1000 mg, preferably between 50 and 500 mg, more preferably between 75 and 100 mg.

14. A pharmaceutical composition or a kit of parts comprising:

an ON capable of causing platelet activation, platelet aggregation and/or thrombus formation in an individual to be treated, at a ON blood plasma concentration of between about 0.01 and 10 μΜ, and

an inhibitor of platelet activation, aggregation or thrombus formation selected from the group consisting of: (i) an inhibitor of collagen (platelet-specific) collagen-receptor interaction, such as an antibody (e.g. anti-GPVI antibody JAQ 1) (ii) a COX1 -inhibitor (e.g. acetylsalicylic acid or a pharmaceutically acceptable salt thereof, or a carbasalate salt); (iii) an inhibitor of the ADP - P2Y12 interaction (iv) an inhibitor of the fibrinogen-GPIIb/IIIa interaction; (v) a NOX- inhibitor, such as NOX1 -inhibitor ML171 , apocynin, or 2-acetylphenothiazine; (vi) an antioxidant, such as vitamin C or diferuloylmethane, or a combination of one or more of (i) to (vi) above.

15. A method, a composition or kit of parts according to any of the previous claims, wherein the ON is selected from the group consisting of the ONs mentioned in Table 1.

16. A method for modifying a first therapeutic oligonucleotide to give a second therapeutic oligonucleotide, wherein (a) the first therapeutic oligonucleotide binds to a target nucleic acid, includes one or more phosphorothioate linkages, and causes platelet activation, platelet aggregation and/or thrombus formation; and

(b) the second therapeutic oligonucleotide binds to the target nucleic acid, includes one or more phosphorothioate linkages, and causes less platelet activation, platelet aggregation and/or thrombus formation than the first therapeutic oligonucleotide,

wherein the method comprises one or more of the following:

(i) where the first therapeutic oligonucleotide is 18 or more nucleotides long, reducing its length to give a second therapeutic oligonucleotide which is less than 18 nucleotides long;

(ii) reducing the total number of phosphorothioate linkages, such that the second therapeutic oligonucleotide has fewer phosphorothioate linkages than the first therapeutic oligonucleotide; and/or

(iii) reducing the number of consecutive phosphorothioate linkages, such that the second therapeutic oligonucleotide has fewer consecutive phosphorothioate linkages than the first therapeutic oligonucleotide.

17. The method of claim 16, wherein option (ii) results in the percentage of phosphorothioate linkages in the second therapeutic oligonucleotide being less than 95%, preferably less than 90%, less than 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, or 30%.

18. The method of claim 16, wherein option (iii) results in the number of consecutive phosphorothioate linkages in the second therapeutic oligonucleotide being 8 or less, preferably 7 or less, 6 or less, 5 or less, 4 or less, or 3 or less.

19. The method of any one of claims 16 to 18, wherein the method comprises: analyzing the number and/or pattern of phosphorothioate linkages in the first therapeutic oligonucleotide; and synthesizing the second therapeutic oligonucleotide.

20. A method for producing an oligonucleotide specific for a target nucleic acid, comprising steps of: (a) preparing a first therapeutic oligonucleotide which binds to a target nucleic acid, includes one or more phosphorothioate linkages; (b) determining the first therapeutic oligonucleotide's ability to cause platelet activation, platelet aggregation and/or thrombus formation; (c) preparing a second therapeutic oligonucleotide which also binds to the target nucleic acid and includes one or more phosphorothioate linkages; (d) determining the second therapeutic oligonucleotide's ability to cause platelet activation, platelet aggregation and/or thrombus formation; and (e) if the second therapeutic oligonucleotide has a lower ability to cause platelet activation, platelet aggregation and/or thrombus formation than the first therapeutic oligonucleotide, synthesizing and purifying the second therapeutic oligonucleotide for use as a pharmaceutical.

21. The method of claim 20, wherein the second therapeutic oligonucleotide has fewer phosphorothioate linkages than the first therapeutic oligonucleotide.

22. The method of claim 20, wherein the second therapeutic oligonucleotide has fewer consecutive phosphorothioate linkages than the first therapeutic oligonucleotide.

23. The method of any one of claims 16 to 22, wherein the nucleotide sequence of the second therapeutic oligonucleotide is the same as, or is a fragment of, the nucleotide sequence of the first therapeutic oligonucleotide.

24. The method of any one of claims 16 to 23, wherein the second therapeutic oligonucleotide is from 10-17 nucleotides long.

25. A method according to any one of claims 16 to 24, wherein the second therapeutic oligonucleotide causes less platelet aggregation compared to the first oligonucleotide, as measured by determining the reduction of OD5 5nm over time, upon incubation of platelet rich plasma (prp) in the presence of said oligonucleotides in an in vitro assay.

26. A method according to claim 25, wherein less platelet aggregation, upon incubation of the prp with the oligonucleotide is defined as (i) a delay in OD5 5nm reduction; (ii) a slower reduction in OD5 5nm per time unit before stabilization of the OD595nm level; (iii) a higher residual OD5 5nm level after the stabilization of the OD595nm level over time, or a combination of any one of (i) to (iii).