MC4RMC4R) gene that encodes the MC4R protein. The RNA editing of the target adenosine, changing an isoleucine residue to a valine residue at position 317 in the protein (I317V), results in a gain-of-function of the MC4R protein, which will result in loss of body weight and lower BMI, thereby lowering the risk of suffering from disorders related to obesity.
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hair-pin or stem-loop structure, and wherein said oligonucleotide comprises a cytidine (a non-complementary nucleotide) or a uridine in a position opposite to the target adenosine to be edited in the target RNA region.
RELN RELN RELN RELN RELN nucleic acid sequence comprising an edited target nucleotide; as well as compositions, vectors, and methods of use related thereto.
The invention relates to the field of RNA editing using antisense oligonucleotides (AONs) that comprise at least one non-naturally occurring internucleoside linkage modification. The RNA editing is directed at deaminating target adenosines in endogenously present RNA nucleic acid molecules, such as pre-mRNA and mRNA transcript products, using deaminating enzymes such as ADAR1 and ADAR2 that are preferably endogenously present in the cell. The non-natural internucleoside linkage modification is a phosphoramidate linkage, preferably a mesyl phosphoramidate (PNms) linkage.
The present invention relates to antisense oligonucleotides (AONs) that can mediate RNA editing by binding to a target RNA nucleic acid molecule, preferably an RNA transcript molecule, in a cell and recruiting an endogenous deaminating enzyme in the cell to deaminate one or more target adenosine nucleotides in the target RNA molecule to an inosine. The target RNA molecule is a transcript molecule form the SLC10A1 gene that encodes the Na+/Taurocholate Co-transporting Polypeptide (NTCP). The RNA editing of the one or more target adenosines will result in a loss-of-function of the NTCP protein, which will result in lowered uptake of bile acids from the portal circulation into the liver, thereby lowering the risk of suffering from disorders related to bile accumulation in the liver.
A61P 1/16 - Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
6.
ANTISENSE OLIGONUCLEOTIDES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
The disclosure relates to the field of diseases caused by a lowered synaptic inhibition, preferably those that are caused by a diminished activity of the potassium (K) / chloride (Cl) cotransporter (KCC2). The disclosure involves oligonucleotides and the use thereof in RNA editing methods in targeting a target adenosine in a codon encoding a phosphorylation site in the KCC2-encoding SLC12A5 pre-mRNA or mRNA, preferably the adenosine in the codon encoding threonine at position 1007 of the KCC2b isoform. Through the editing the threonine is replaced by an alanine, thereby removing the phosphorylation site, and thereby increasing the activity of the KCC2 protein in the process of restoring GABAergic inhibitory tone. The disclosure further relates to oligonucleotides for use in the treatment of chronic pain and epilepsy.
ANGPTL3ANGPTL3 transcript in a cell, preferably a liver cell, more preferably a hepatocyte, to yield an ANGPTL3 protein that has a diminished or lowered ability to inhibit lipolysis, because of the RNA editing.
42 - Scientific, technological and industrial services, research and design
Goods & Services
Scientific research; scientific research consulting; scientific research and development; scientific research and development in the field of mRNA therapy; drug discovery services; testing, inspection, research, or development of pharmaceutical preparations for mRNA therapy; pharmaceutical research and development; pharmaceutical products development; development of pharmaceutical preparations and medicines; pharmaceutical drug development services; consulting services in the field of pharmaceutical research and development; research and development services in the field of pharmaceutical preparations; research and development of new pharmaceutical products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Scientific research; scientific research consulting; scientific research and development; scientific research and development in the field of mRNA therapy; drug discovery services; testing, inspection, research, or development of pharmaceutical preparations for mRNA therapy; pharmaceutical research and development; pharmaceutical products development; development of pharmaceutical preparations and medicines; pharmaceutical drug development services; consulting services in the field of pharmaceutical research and development; research and development services in the field of pharmaceutical preparations; research and development of new pharmaceutical products
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA sequence in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a non-complementary nucleotide in a position opposite to the nucleotide to be edited in the target RNA sequence.
The invention relates to the field of medicine and to the field of RNA editing, wherein a target adenosine present in a target RNA molecule in a cell is deaminated to an inosine by an endogenous ADAR enzyme that is recruited by a double-stranded complex generated between an administered RNA editing producing antisense oligonucleotide (EON) and a region of the target RNA molecule that comprises the target adenosine. The invention relates to the improved delivery of the EON to the target cell using a triterpene glycoside purified from seeds of Agrostemma githago L.
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
A61K 31/704 - Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin, digitoxin
A61K 47/54 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
The invention relates to nucleic acid molecules for pseudouridylation of a target uridine in a target RNA in a mammalian cell, wherein the nucleic acid molecule comprises a guide region capable of forming a partially double stranded nucleic acid complex with the target RNA comprising the target uridine, wherein the partially double stranded nucleic acid complex is capable of engaging a mammalian pseudouridylation enzyme, wherein the guide region assists in positioning the target uridine in the partially double stranded nucleic acid complex for it to be converted to a pseudouridine by the mammalian pseudouridylation enzyme.
The invention relates to the field of diseases caused by alcohol intolerance, such as those that are the result of an ALDH2*2 mutation in the human ALDH2 gene. The invention involves oligonucleotides and the use thereof in RNA editing methods in targeting a target adenosine in an endogenous human ALDH2 transcript in a cell, such as a G>A mutation in the transcript molecule of a mutant ALDH2 gene coding for a mutant p.E504K ALDH2 protein, especially in the liver.
The invention relates to antisense oligonucleotides (AON) for use in the prevention, treatment, or amelioration of a corneal dystrophy caused by a (mutated) TGFBI gene. More specifically, the invention relates to gapmers for use in the downregulation of TGFBI mRNA expression and/or TGFBI protein expression, thereby preventing, treating, or ameliorating the TGFBI-related corneal dystrophy. The AONs of the present invention prevent or inhibit the occurrence of corneal deposits due to (mutated) TGFBI genes.
RNA editing is achieved using oligonucleotide constructs comprising (i) a targeting portion specific for a target nucleic acid sequence to be edited and (ii) a recruiting portion capable of binding and recruiting a nucleic acid editing entity naturally present in the cell. The nucleic acid editing entity, such as ADAR, is redirected to a preselected target site by means of the targeting portion, thereby promoting editing of preselected nucleotide residues in a region of the target RNA which corresponds to the targeting portion.
The invention relates to a heteroduplex RNA editing oligonucleotide complex (HEON) comprising a first nucleic acid strand annealed to a second nucleic acid strand, for use in the targeted deamination of a target adenosine present in a target RNA molecule, wherein the first nucleic acid strand is capable of hybridizing to a stretch within the target RNA molecule that includes the target adenosine, and thereby forms a double-stranded nucleic acid complex that can recruit an enzyme with deaminase activity to deaminate the target adenosine to an inosine. The first nucleic acid strand and/or the second nucleic acid strand in the HEON is bound to a hydrophobic moiety, and optionally to a cell-targeting ligand.
The invention relates to antisense oligonucleotides that can form a double stranded nucleic acid complex with a target RNA molecule, wherein the double stranded nucleic acid complex is capable of recruiting an adenosine deaminating enzyme for deamination of a target adenosine in the target RNA molecule, wherein the nucleotide in the AON that is directly opposite the target adenosine comprises a 2',2'-disubstitution, preferably a 2',2'-difluro substitution in the ribose moiety.
The invention relates to antisense oligonucleotides that can form a double stranded nucleic acid complex with a target RNA molecule, wherein the double stranded nucleic acid complex is capable of recruiting an adenosine deaminating enzyme for deamination of a target adenosine in the target RNA molecule, wherein the nucleotide directly 5' of the target adenosine in the target RNA molecule is a guanosine (5'-G), and wherein the nucleotide in the AON that is opposite the guanosine is a nucleotide analog that can induce a syn conformation of the guanosine.
The invention relates to a composition comprising a set of two single stranded antisense oligonucleotides (AONs), wherein one AON is the ‘Editing AON’ and the other AON is the ‘Helper AON’, for use in the deamination of a target adenosine in a target RNA to an inosine, wherein the Editing AON is complementary to a stretch of nucleotides in the target RNA that includes the target adenosine, wherein the Helper AON is complementary to a stretch of nucleotides in the target RNA that is separate from the stretch of nucleotides that is complementary to the Editing AON, wherein the Helper AON has a length of 16 to 22 nucleotides and the Editing AON has a length of 16 to 22 nucleotides.
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a cytidine (a non-complementary nucleotide) or a uridine in a position opposite to the target adenosine to be edited in the target RNA region.
The invention relates to guide oligonucleotides that can bring about specific changes to a target RNA or DNA molecule in a eukaryotic cell, preferably liver cells, for use in the treatment of hypercholesterolemia, cardiovascular disease, liver injury and/or alcohol- induced steatohepatitis in human subjects. More specifically, the invention relates to guide oligonucleotides and the use thereof in the editing of nucleic acids encoding an auto-cleavage site within the PCSK9 proprotein, thereby inhibiting, or inactivating the PCSK9 protein (or the matured PCSK9 complex) in its ability to cause LDL receptor protein degradation.
An antisense oligonucleotide (AON) capable of inhibiting ADAR-mediated deamination of a target adenosine present in an editing-site sequence (ESS) of a target RNA molecule, wherein under physiological conditions the ESS would hybridize with an editing-site complementary sequence (ESCS) of an RNA molecule to form a double stranded RNA complex, wherein the AON comprises a sequence configured to compete with the ESCS for hybridization with the ESS.
The invention relates to the fields of medicine and to antisense oligonucleotides (AONs) that are capable of skipping exon 50 from human USH2A pre-mRNA and that may be used in the treatment, prevention and/or delay of Usher syndrome type II and/or USH2A-associated non syndromic retina degeneration.
The invention relates to RNA editing oligonucleotides (EONs) that can bring about specific editing of a target nucleotide (adenosine) in a target RNA molecule in a eukaryotic cell, wherein said oligonucleotide is for use in the treatment of Stargardt disease, and more preferably for the deamination of target adenosines present in the ABCA4 pre-mRNA or ABCA4 mRNA.
The invention relates to single-stranded RNA editing antisense oligonucleotides (AONs) for binding to a target RNA molecule for deaminating a target nucleotide, preferably an adenosine, present in the target RNA molecule and recruiting, in a cell, preferably a human cell, an enzyme with nucleotide deamination activity, preferably an ADAR enzyme, to deaminate the target nucleotide in the target RNA molecule. The AONs carry at least one methylphosphonate-modified internucleosidic linkage on a position that would render the AON more stable in comparison to an AON not carrying that methylphosphonate modification at that position.
The invention relates to single-stranded RNA editing antisense oligonucleotides (AO Ns) for binding to a target RNA molecule for deaminating at least one target adenosine present in the target RNA molecule and recruiting, in a cell, preferably a human cell, an ADAR2 enzyme, to deaminate the at least one target adenosine in the target RNA molecule. The AON according to the invention comprises a cytidine analog at the position opposite the target adenosine, wherein the cytidine analog serves as an H-bond donor at the N3 site, for more efficient RNA editing.
The invention relates to the fields of medicine. In particular, it relates to novel antisense oligonucleotides (AONs) that are capable of skipping exon 62 from human USH2A premRNA and that may be used in the treatment, prevention and/or delay of Usher syndrome type II and/or USH2A-associated non syndromic retina degeneration.
The invention relates to antisense oligonucleotides (AON) capable of inducing the skip of at least exon 3 from (human) CD274 pre-mRNA to render a shortened PD-L1 protein, and thereby modulating the function of PD-L1. Preferably, PD-L1 that is produced after the skip of exon 3 from its pre-mRNA is no longer able to traffic to the cell membrane and/or is no longer able to (fully) interact with its receptor PD-1. The result is preferably that the PD-1/PD-L1 pathway is blocked and T cell exhaustion is diminished, prevented or lowered. The AONs of the present invention are particularly useful in immunotherapy and can be applied in the treatment, prevention, and amelioration of (acute or chronic) viral infections, cancer and (auto-) immune disease, especially those disorders in which T cell exhaustion plays a role. The invention relates to AONs, pharmaceutical compositions comprising such AONs, and viral vectors expressing such AONs, that may be used in the treatment of subjects that may benefit from modulation of PD-L1 function.
ABCA4 ABCA4 pre-mRNA. The AONs of the present invention target sequences within exon 17 and/or surrounding sequences in intron 16 and intron 17. The AONs of the present invention are applicable in treating a human subject suffering from a disorder caused by a mutation in the ABCA4 gene, preferably mutations affecting exon 17, more preferably the c.2588G>C mutation at the 5' terminus of exon 17.
The invention relates to editing oligonucleotides (EONs) for binding to a target nucleic acid and recruiting an enzyme with nucleotide deamination activity to edit the target nucleic acid. The EONs carry phosphonoacetate internucleotide linkage modifications and/or unlocked nucleic acid (UNA) ribose modifications at specified positions and do not carry such modifications on positions that would lower nucleic acid editing efficiency. The selection of positions that should or should not carry a modification is based on computational modelling that revealed incompatibilities of the modifications with the enzyme with nucleotide deamination activity.
The invention relates to RNA editing oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA molecule in a eukaryotic cell, wherein said oligonucleotide is for use in the treatment of Usher syndrome, and more preferably for the deamination of target adenosines that are part of a premature stop codon present in the USH2A pre-mRNA or USH2A mRNA.
The invention relates to antisense oligonucleotides (AON) capable of inducing the skip of exon 36 from human CEP290 pre-mRNA. The c.4723A>T mutation in the human CEP290 gene is the cause of Leber's Congenital Amaurosis type 10 (LCA10) in patients carrying this mutation. The AONs of the present invention can be used in the treatment of LCA10 caused by mutations in exon 36, such as the c.4723A>T mutation. The invention relates to AONs, pharmaceutical formulations comprising such AONs, and viral vectors expressing such AONs, that may be used in the treatment of LCA10.
The invention relates to a composition comprising a set of two single stranded antisense oligonucleotides (AONs), wherein one AON is the 'Editing AON' and the other AON is the 'Helper AON', for use in the deamination of a target adenosine in a target RNA to an inosine, wherein the Editing AON is complementary to a stretch of nucleotides in the target RNA that includes the target adenosine, wherein the Helper AON is complementary to a stretch of nucleotides in the target RNA that is separate from the stretch of nucleotides that is complementary to the Editing AON, wherein the Helper AON has a length of 16 to 22 nucleotides and the Editing AON has a length of 16 to 22 nucleotides.
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a cytidine (a non-complementary nucleotide) or a uridine in a position opposite to the target adenosine to be edited in the target RNA region.
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA sequence in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a non-complementary nucleotide in a position opposite to the nucleotide to be edited in the target RNA sequence.
The invention relates to editing oligonucleotides (EONs) that carry stereospecific phosphorothioate internucleotide linkage modifications at specified positions and that do not carry such modifications on positions that would lower RNA editing efficiency. The selection of positions that should or should not carry a phosphorothioate Rp and/or Sp configuration modification is based on computational modelling that revealed incompatibilities of the stereospecific linkages with the intermolecular oxygen-mediated hydrogen bond network.
The invention relates to the fields of medicine and biotechnology. In particular, it relates to novel antisense oligonucleotides (AONs) that may be used in the treatment, prevention and/or delay of Stargardt disease and/or ABCA4-associated eye disease. More in particular, the invention relates to AONs that are used in inhibiting or blocking exon 39 skipping in the human ABCA4 pre-mRNA.
The invention relates to ophthalmic compositions comprising: i) a nucleic acid molecule, preferably an antisense oligonucleotide, such as an single-stranded antisense oligonucleotide that modulates splice modulation or prevention of RNA toxicity due to trinucleotide repeats in a target RNA molecule, or a gapmer that induces breakdown of a target RNA molecule after formation of a double-stranded RNA/gapmer complex; and ii) a viscosifying polymer. The ophthalmic compositions are for topical administration in the eye of a mammalian subject suffering from a corneal disease, such as a hereditary corneal dystrophy. The viscosifying polymer in the compositions of the invention allows the entry of the nucleic acid molecule to the different layers of the cornea: the corneal epithelium, Bowman's membrane, stroma, Dua's layer, the Descemet's membrane and/or the corneal endothelium.
The invention relates to nucleic acid molecules for pseudouridylation of a target uridine in a target RNA in a mammalian cell, wherein the nucleic acid molecule comprises a guide region capable of forming a partially double stranded nucleic acid complex with the target RNA comprising the target uridine, wherein the partially double stranded nucleic acid complex is capable of engaging a mammalian pseudouridylation enzyme, wherein the guide region assists in positioning the target uridine in the partially double stranded nucleic acid complex for it to be converted to a pseudouridine by the mammalian pseudouridylation enzyme.
C07H 21/04 - Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
45.
DELIVERY OF NUCLEIC ACIDS FOR THE TREATMENT OF AUDITORY DISORDERS
The invention relates to the delivery of therapeutic compounds to the inner ear for the treatment of auditory disorders. In one aspect, it relates to compositions comprising: i) a thermo-reversible (or thermosensitive) polymer gel and ii) a nucleic acid molecule (such as a single-stranded AON or a gapmer), for the delivery of the nucleic acid molecule to cells within the inner ear, such as the hair cells in the cochlea, for the treatment, prevention and/or delay of hearing impairment or hearing loss. The nucleic acid molecules are preferably applicable for modulation of splicing and/or gene expression.
The invention relates to single-stranded RNA editing antisense oligonucleotides (AO Ns) for binding to a target RNA molecule for deaminating at least one target adenosine present in the target RNA molecule and recruiting, in a cell, preferably a human cell, an ADAR2 enzyme, to deaminate the at least one target adenosine in the target RNA molecule. The AON according to the invention comprises a cytidine analog at the position opposite the target adenosine, wherein the cytidine analog serves as an H-bond donor at the N3 site, for more efficient RNA editing.
An antisense oligonucleotide (AON) capable of inhibiting ADAR-mediated deamination of a target adenosine present in an editing-site sequence (ESS) of a target RNA molecule, wherein under physiological conditions the ESS would hybridize with an editing-site complementary sequence (ESCS) of an RNA molecule to form a double stranded RNA complex, wherein the AON comprises a sequence configured to compete with the ESCS for hybridization with the ESS.
The invention relates to single-stranded RNA editing antisense oligonucleotides (AONs) for binding to a target RNA molecule for deaminating a target nucleotide, preferably an adenosine, present in the target RNA molecule and recruiting, in a cell, preferably a human cell, an enzyme with nucleotide deamination activity, preferably an ADAR enzyme, to deaminate the target nucleotide in the target RNA molecule. The AONs carry at least one methylphosphonate-modified internucleosidic linkage on a position that would render the AON more stable in comparison to an AON not carrying that methylphosphonate modification at that position.
The invention relates to antisense oligonucleotides (AON) capable of inducing the skip of at least exon 3 from (human) CD274 pre-mRNA to render a shortened PD-L1 protein, and thereby modulating the function of PD-L1. Preferably, PD-L1 that is produced after the skip of exon 3 from its pre-mRNA is no longer able to traffic to the cell membrane and/or is no longer able to (fully) interact with its receptor PD-1. The result is preferably that the PD-1/PD-L1 pathway is blocked and T cell exhaustion is diminished, prevented or lowered. The AONs of the present invention are particularly useful in immunotherapy and can be applied in the treatment, prevention, and amelioration of (acute or chronic) viral infections, cancer and (auto-) immune disease, especially those disorders in which T cell exhaustion plays a role. The invention relates to AONs, pharmaceutical compositions comprising such AONs, and viral vectors expressing such AONs, that may be used in the treatment of subjects that may benefit from modulation of PD-L1 function.
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
A61K 31/7125 - Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
A61K 31/712 - Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
C07H 21/02 - Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
A61P 31/00 - Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
51.
ANTISENSE OLIGONUCLEOTIDES FOR NUCLEIC ACID EDITING
The invention relates to editing oligonucleotides (EONs) for binding to a target nucleic acid and recruiting an enzyme with nucleotide deamination activity to edit the target nucleic acid. The EONs carry phosphonoacetate internucleotide linkage modifications and/or unlocked nucleic acid (UNA) ribose modifications at specified positions and do not carry such modifications on positions that would lower nucleic acid editing efficiency. The selection of positions that should or should not carry a modification is based on computational modelling that revealed incompatibilities of the modifications with the enzyme with nucleotide deamination activity.
The invention relates to antisense oligonucleotides (AON) capable of inducing the skip of exon 36 from human CEP290 pre-mRNA. The c.4723A>T mutation in the human CEP290 gene is the cause of Leber's Congenital Amaurosis type 10 (LCA10) in patients carrying this mutation. The AONs of the present invention can be used in the treatment of LCA10 caused by mutations in exon 36, such as the c.4723A>T mutation. The invention relates to AONs, pharmaceutical formulations comprising such AONs, and viral vectors expressing such AONs, that may be used in the treatment of LCA10.
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
A61K 31/7125 - Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
C07H 21/02 - Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
The invention relates to the fields of medicine and immunology. In particular, it relates to novel antisense oligonucleotides that may be used in the treatment, prevention and/or delay of Usher Syndrome type II and/or USH2A-associated non syndromic retina degeneration, especially by skipping a pseudo exon (PE40) between exon 40 and 41 in the human USH2Agene.
RNA editing is achieved using oligonucleotide constructs comprising (i) a targeting portion specific for a target nucleic acid sequence to be edited and (ii) a recruiting portion capable of binding and recruiting a nucleic acid editing entity naturally present in the cell. The nucleic acid editing entity, such as ADAR, is redirected to a preselected target site by means of the targeting portion, thereby promoting editing of preselected nucleotide residues in a region of the target RNA which corresponds to the targeting portion.
The invention relates to the fields of medicine and immunology. In particular, it relates to novel antisense oligonucleotides that may be used in the treatment, prevention and/or delay of Usher Syndrome type II and/or USH2A-associated non syndromic retina degeneration, especially by skipping a pseudo exon (PE40) between exon 40 and 41 in the human USH2A gene.
The invention relates to editing oligonucleotides (EONs) that carry stereospecific phosphorothioate internucleotide linkagemodifications at specified positions and that do not carry such modifications on positions that would lower RNA editing efficiency. The selection of positions that should or should not carry a phosphorothioate Rp and/or Sp configurationmodification is based on computational modelling that revealed incompatibilitiesof thestereospecific linkages with the intermolecular oxygen-mediated hydrogen bond network.
The invention relates to double stranded oligonucleotide complexes comprising an antisense oligonucleotide (AON) and a complementary sense oligonucleotide (SON), for use in the deamination of a target adenosine in a sense target RNA sequence in a cell by an ADAR enzyme, wherein at least the nucleotide in the AON that is directly opposite the target adenosine in the target RNA sequence does not have a 2′-O-alkyl modification and the SON comprises nucleotides that are at least complementary to all nucleotides in the AON that do not have a 2′-O-alkyl modification. The invention further relates to methods of RNA editing using the AON/SON complexes of the invention.
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a cytidine (a non-complementary nucleotide) or a uridine in position opposite to the target adenosine to be edited in the target RNA region.
The invention relates to nucleic acid molecules for pseudouridylation of a target uridine in a target RNA in a mammalian cell, wherein the nucleic acid molecule comprises a guide region capable of forming a partially double stranded nucleic acid complex with the target RNA comprising the target uridine, wherein the partially double stranded nucleic acid complex is capable of engaging a mammalian pseudouridylation enzyme, wherein the guide region assists in positioning the target uridine in the partially double stranded nucleic acid complex for it to be converted to a pseudouridine by the mammalian pseudouridylation enzyme.
The invention relates to editing oligonucleotides (EONs) that carry 2'-0-methoxyethyl (2'-MOE) ribose modifications at specified positions and that do not carry such modifications on positions that would lower RNA editing efficiency. The selection of positions that should or should not carry a 2'-MOE modification is based on computational modelling that revealed steric clashes between the 2'-MOE modification and mammalian ADAR enzymes.
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA sequence in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a non-complementary nucleotide in a position opposite to the nucleotide to be edited in the target RNA sequence.
RNA editing is achieved using oligonucleotide constructs comprising (i) a targeting portion specific for a target nucleic acid sequence to be edited and (ii) a recruiting portion capable of binding and recruiting a nucleic acid editing entity naturally present in the cell. The nucleic acid editing entity, such as ADAR, is redirected to a preselected target site by means of the targeting portion, thereby promoting editing of preselected nucleotide residues in a region of the target RNA which corresponds to the targeting portion.
The invention relates to the fields of medicine and biotechnology. In particular, it relates to novel antisense oligonucleotides (AONs) that may be used in the treatment, prevention and/or delay of Stargardt disease and/or ABCA4-associated eye disease. More in particular, the invention relates to AONs that are used in inhibiting or blocking exon 39 skipping in the human ABCA4 pre-mRNA.
The invention relates to antisense oligonucleotides (AONs) comprising repetitive trinucleotide units for use in the treatment or prevention of genetic eye diseases, preferably eye dystrophy disorders caused by RNA toxicity such as Fuch's Endothelial Corneal Dystrophy (FECD). The oligonucleotides of the present invention are used to target trinucleotide repeat (TNR) sequence expansions present in intron sequences, to prevent the disease-related sequestration of cellular proteins that interact with such TNR expansions.
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 31/7105 - Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
The invention relates to double stranded oligonucleotide complexes comprising an antisense oligonucleotide (AON) and a complementary sense oligonucleotide (SON), for use in the deamination of a target adenosine in asense target RNA sequence in a cell by an ADAR enzyme, wherein at least the nucleotide in the AON that is directly opposite the target adenosine in the target RNA sequence does not have a 2'-O-alkyl modification and the SON comprises nucleotides that are at least complementary to all nucleotides in the AON that do not have a 2'-O-alkyl modification. The invention further relates to methods of RNA editing using the AON/SON complexes of the invention.
The invention relates to the fields of medicine and immunology. In particular, it relates to novel antisense oligonucleotides (AONs) that may be used in the treatment, prevention and/or delay of Usher syndrome type II and/or USH2A-associated non syndromic retina degeneration.
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA sequence in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a non-complementary nucleotide in a position opposite to the nucleotide to be edited in the target RNA sequence.
The invention relates to antisense oligonucleotides that are capable of bringing about specific editing of a target nucleotide (adenosine) in a target RNA in a eukaryotic cell, wherein said oligonucleotide does not, in itself, form an intramolecular hairpin or stem-loop structure, and wherein said oligonucleotide comprises a cytidine (a non-complementary nucleotide) or a uridine in a position opposite to the target adenosine to be edited in the target RNA region.
The invention relates to the fields of medicine and immunology. In particular, it relates to novel antisense oligonucleotides that may be used in the treatment, prevention and/or delay of Usher Syndrome type II and/or USH2A-associated non syndromic retina degeneration, especially by skipping a pseudo exon (PE40) between exon 40 and 41 in the human USH2Agene.
The invention relates to new (preferably single stranded antisense) oligonucleotides that can be used in the prevention or treatment of Friedreich's ataxia. In a preferred aspect, the oligonucleotides comprise at least 51 nucleotides and further comprise single or multiple modified nucleotides and/or modified internucleoside linkages. The invention further relates to the use of said oligonucleotides in methods of preventing or treating Friedreich's ataxia.
Theinvention relates to oligonucleotides suitable for use in treating human disease. More in particular the inventionrelates to antisense oligonucleotides suitable for the treatment of Alzheimer's disease.
The invention relates to antisense oligonucleotides (AONs) comprising repetitive trinucleotide units for use in the treatment or prevention of genetic eye diseases, preferably eye dystrophy disorders caused by RNA toxicity such as Fuch's Endothelial Corneal Dystrophy (FECD). The oligonucleotides of the present invention are used to target trinucleotide repeat (TNR) sequence expansionspresent in intron sequences, to prevent the disease-related sequestration of cellular proteins that interact withsuch TNR expansions.
An antisense oligonucleotide capable of preventing or reducing exon 80 inclusion into a human COL7A1 mRNA, and methods for preventing or reducing exon 80 inclusion into a human COL7A1 mRNA.
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.
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Chemical compounds for scientific or research purposes. Pharmaceutical preparations for the treatment, diagnosis and
prevention of genetic diseases and disorders; pharmaceutical
preparations for the treatment of genetic diseases based on
oligonucleotides, oligoribonucleotides, aptamers, nucleic
acid molecules, dna, rna, polynucleotides, ribozymes,
mirnas, snornas, mrnas or sirnas. Laboratory research services relating to pharmaceuticals;
medical research; pharmaceutical research and development;
laboratory research and analysis in the field of medicines;
services of biotechnological, chemical and pharmacological
laboratories, including scientific and technological
research, in relation to the production of chemicals and
biotechnological products for use in the preparation of
pharmaceuticals; development of pharmaceutical preparations
and medicines; development of technologies for the
production of pharmaceutical semi finished and/or finished
preparations; academic research, medical and biochemical
research and development services; chemistry, laboratory
technicians' and engineering services; research and
development in the field of biotechnology; research into and
development and testing of pharmaceutical and biochemical
semi- finished products, in particular for use in medicines,
research into and development and testing of medicines;
development of test systems for pharmaceutical, medical and
sanitizing preparations; services development and
identification of and research into new drug targets.
78.
OLIGONUCLEOTIDES MATCHING COL7A1 EXON 73 FOR EPIDERMOLYSIS BULLOSA THERAPY
Antisense oligonucleotides capable of preventing or reducing exon 73 inclusion into the human COL7A mRNA are characterized in various ways: (a) the oligonucleotide's sequence includes at most two CpG sequences; (b) the oligonucleotide has a length of no more than 24 nucleotides; (c) the oligonucleotide is capable of annealing to the (SRp40/SC35 binding / ESE) element in exon73. These oligonucleotides can usefully be oligoribonucleotides with modified internucleosidic linkages e.g. phosphorothioate linkages.
Antisense oligonucleotides target the mutation in intron 26 of the CEP290 gene and reduce inclusion of the aberrant exon into the CEP290 mRNA. The oligonucleotides include no more than 3 consecutive guanosines, have no more than 60% guanosine nucleobases, include at most one CpG sequence, and/or do not have the potential to form a hairpin comprising 3 or more consecutive complementary base pairs.
RNA editing is achieved using oligonucleotide constructs comprising (i) a targeting portion specific for a target nucleic acid sequence to be edited and (ii) a recruiting portion capable of binding and recruiting a nucleic acid editing entity naturally present in the cell. The nucleic acid editing entity, such as ADAR, is redirected to a preselected target site by means of the targeting portion, thereby promoting editing of preselected nucleotide residues in a region of the target RNA which corresponds to the targeting portion.
A method for making a change in an endogenous chromosomal DNA sequence of a mammalian cell, comprising steps of: (i) introducing into said cell an oligonucleotide having a sequence that is complementary to the chromosomal DNA sequence and that includes the change; (ii) allowing sufficient time for the cell to incorporate the change into the endogenous chromosomal DNA sequence through endogenous nucleic acid modifying pathways; and (iii) identifying the presence of the change in the chromosomal DNA sequence. The invention is particularly useful for correcting mutations in the CFTR gene.
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Chemical compounds for scientific or research purposes. Pharmaceutical and veterinary preparations; sanitary
preparations for medical purposes; dietetic substances
adapted for medical use. Laboratory research services relating to pharmaceuticals;
medical research; pharmaceutical research and development;
research and analysis in the field of medicine; services of
biotechnological, chemical and pharmacological laboratories,
including scientific and technological research, in relation
to the production of chemicals and biotechnological products
for use in the preparation of pharmaceuticals; development
of pharmaceutical preparations and medicines; development of
technologies for the production of pharmaceutical semi
finished and/or finished preparations; academic research,
research services in the medical and biochemical field;
chemistry, laboratory technicians' and engineering services;
research and development in the field of biotechnology;
research into and development and testing of pharmaceutical
and biochemical semi-finished products, in particular for
use in medicines, research into and development and testing
of medicines; development of test systems for
pharmaceutical, medical and sanitizing preparations;
services of development and identification of and research
into new drug targets.
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
[ Chemical compounds for scientific or research purposes ] Pharmaceutical preparations for the prevention and treatment of genetic and congenital disorders, metabolic disorders, infectious diseases, cancer and pain relief [ ; veterinary preparations for the prevention and treatment of genetic and congenital disorders, metabolic disorders, infectious diseases, cancer and pain relief; sanitary preparations for medical purposes; dietetic substances, namely, sugar and sugar substitutes adapted for medical use ] [ Laboratory research services relating to pharmaceuticals; medical research; pharmaceutical research and development; research and analysis in the field of medicine; biotechnological, chemical and pharmacological laboratory services, namely, scientific and technological research in the field of the production of chemicals and biotechnological products for use in the preparation of pharmaceuticals; development of pharmaceutical preparations and medicines; development of technologies for the production of pharmaceutical semi-finished and/or finished preparations; academic research services in the medical and biochemical field; laboratory technician services, namely, research and analysis in the field of chemistry; engineering services; research and development in the field of biotechnology; research, development and testing of pharmaceutical and biochemical semi-finished products, in particular for use in medicines; research, development and testing of medicines; development of test systems for pharmaceutical, medical and sanitizing preparations; research and development services relating to new drug targets ]
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Chemical compounds for scientific or research purposes. Pharmaceutical and veterinary preparations; sanitary
preparations for medical purposes; dietetic substances
adapted for medical use. Laboratory research services relating to pharmaceuticals;
medical research; pharmaceutical research and development;
research and analysis in the field of medicine; services of
biotechnological, chemical and pharmacological laboratories,
including scientific and technological research, in relation
to the production of chemicals and biotechnological products
for use in the preparation of pharmaceuticals; development
of pharmaceutical preparations and medicines; development of
technologies for the production of pharmaceutical semi
finished and/or finished preparations; academic research,
services in the medical and biochemical field; chemistry,
laboratory technicians' and engineering services; research
and development in the field of biotechnology; research into
and development and testing of pharmaceutical and
biochemical semi-finished products, in particular for use in
medicines, research into and development and testing of
medicines; development of test systems for pharmaceutical,
medical and sanitizing preparations; services development
and identification of and research into new drug targets.
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Chemical compounds for scientific or research purposes. Pharmaceutical and veterinary preparations; sanitary preparations for medical purposes; dietetic substances adapted for medical use. Laboratory research services relating to pharmaceuticals; medical research; pharmaceutical research and development; research and analysis in the field of medicine; services of biotechnological, chemical and pharmacological laboratories, including scientific and technological research, in relation to the production of chemicals and biotechnological products for use in the preparation of pharmaceuticals; development of pharmaceutical preparations and medicines; development of technologies for the production of pharmaceutical semi finished and/or finished preparations; academic research, research services in the medical and biochemical field; chemistry, laboratory technicians' and engineering services; research and development in the field of biotechnology; research into and development and testing of pharmaceutical and biochemical semi-finished products, in particular for use in medicines, research into and development and testing of medicines; development of test systems for pharmaceutical, medical and sanitizing preparations; services development and identification of and research into new drug targets.
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Chemical compounds for scientific or research purposes. Pharmaceutical and veterinary preparations; sanitary preparations for medical purposes; dietetic substances adapted for medical use. Laboratory research services relating to pharmaceuticals; medical research; pharmaceutical research and development; research and analysis in the field of medicine; services of biotechnological, chemical and pharmacological laboratories, including scientific and technological research, in relation to the production of chemicals and biotechnological products for use in the preparation of pharmaceuticals; development of pharmaceutical preparations and medicines; development of technologies for the production of pharmaceutical semi finished and/or finished preparations; academic research services in the medical and biochemical field; chemistry, laboratory technicians' and engineering services; research and development in the field of biotechnology; research into and development and testing of pharmaceutical and biochemical semi-finished products, in particular for use in medicines, research into and development and testing of medicines; development of test systems for pharmaceutical, medical and sanitizing preparations; services development and identification of and research into new drug targets.
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Chemical compounds for scientific or research purposes. Pharmaceutical and veterinary preparations; sanitary
preparations for medical purposes; dietetic substances
adapted for medical use. Laboratory research services relating to pharmaceuticals;
medical research; pharmaceutical research and development;
research and analysis in the field of medicine; services of
biotechnological, chemical and pharmacological laboratories,
including scientific and technological research, in relation
to the production of chemicals and biotechnological products
for use in the preparation of pharmaceuticals; development
of pharmaceutical preparations and medicines; development of
technologies for the production of pharmaceutical semi
finished and/or finished preparations; academic research,
services in the medical and biochemical field; chemistry,
laboratory technicians' and engineering services; research
and development in the field of biotechnology; research,
development and testing of pharmaceutical and biochemical
semi-finished products, in particular for use in medicines;
research, development and testing of medicines; development
of test systems for pharmaceutical, medical and sanitizing
preparations; research and development services relating to
new drug targets.
The present invention relates to the field of gene therapy, more specifically to the use of stabilized artificial RNA molecules for trans-splicing reactions to replace faulty exons for healthy exons. The present invention further relates to the use of the stabilized RNA molecules for treatment of genetic diseases.
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
[ Chemical compounds for scientific or research purposes ] Pharmaceutical preparations for the prevention and treatment of genetic and congenital disorders, metabolic disorders, infectious diseases, cancer and pain relief [ ; veterinary preparations for the prevention and treatment of genetic and congenital disorders, metabolic disorders, infectious diseases, cancer and pain relief; sanitary preparations for medical purposes; dietetic substances, namely, sugar and sugar substitutes adapted for medical use ] [ Laboratory research services relating to pharmaceuticals; medical research; pharmaceutical research and development; research and analysis in the field of medicine; biotechnological, chemical and pharmacological laboratory services, namely, scientific and technological research in the field of the production of chemicals and biotechnological products for use in the preparation of pharmaceuticals; development of pharmaceutical preparations and medicines; development of technologies for the production of pharmaceutical semi-finished and finished preparations; academic research services in the medical and biochemical field; laboratory technician services, namely, research and analysis in the field of chemistry; engineering services; research and development in the field of biotechnology; research, development and testing of pharmaceutical and biochemical semi-finished products, in particular for use in medicines; research, development and testing of medicines; development of test systems for pharmaceutical, medical and sanitizing preparations; research and development services relating to new drug targets ]
01 - Chemical and biological materials for industrial, scientific and agricultural use
05 - Pharmaceutical, veterinary and sanitary products
42 - Scientific, technological and industrial services, research and design
Goods & Services
Chemical compounds for scientific or research purposes. Pharmaceutical and veterinary preparations; sanitary preparations for medical purposes; dietetic substances adapted for medical use. Laboratory research services relating to pharmaceuticals; medical research; pharmaceutical research and development; research and analysis in the field of medicine; services of biotechnological, chemical and pharmacological laboratories, including scientific and technological research, in relation to the production of chemicals and biotechnological products for use in the preparation of pharmaceuticals; development of pharmaceutical preparations and medicines; development of technologies for the production of pharmaceutical semi finished and/or finished preparations; academic research, services in the medical and biochemical field; chemistry, laboratory technicians' and engineering services; research and development in the field of biotechnology; research into and development and testing of pharmaceutical and biochemical semi-finished products, in particular for use in medicines, research into and development and testing of medicines; development of test systems for pharmaceutical, medical and sanitizing preparations; services development and identification of and research into new drug targets.
