Products and compositions
Inventors
DAMES, Sibylle • SCHAEPER, UTE • HAUPTMANN, Judith • Frauendorf, Christian • Bethge, Lucas • WEINGÄRTNER, Adrien
Assignees
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Publication Number
US-11174483-B2
Publication Date
2021-11-16
Expiration Date
Abstract
The present invention relates to products and compositions and their uses. In particular the invention relates to nucleic acid products that interfere with the TMPRSS6 gene expression or inhibits its expression and therapeutic uses such as for the treatment of hemochromatosis, porphyria and blood disorders such as β-thalassemias, sickle cell disease and transfusional iron overload or myelodysplastic syndrome.
Core Innovation
The invention relates to a nucleic acid for inhibiting expression of TMPRSS6. It comprises at least one duplex region having a first strand and a second strand that is at least partially complementary, where the first strand is at least partially complementary to RNA transcribed from the TMPRSS6 gene. The first strand has 5′-3′: aaccagaagaagcagguga (SEQ ID NO: 333), and one or more nucleotides on the first strand, the second strand, or both strands are modified to form modified nucleotides.
The disclosure emphasizes chemical modification of duplex-forming nucleotides to create nuclease-resistant nucleic acids. Modification options include altered sugar stereochemistry, including arabinose, abasic sugars, 2′ modifications, and nucleotide backbone replacements using non-phosphorus connectors and nuclease-resistant surrogates such as morpholino and PNA. Terminal modifications and linkage features are also described, including terminal phosphate analogs and terminal phosphorothioate or phosphorodithioate linkage patterns.
In addition, the invention describes modification-pattern rules between the two strands, including alternating odd/even nucleotide modifications and shifted modifications between strands. The disclosure further describes conjugatable ligand architectures, particularly multivalent GalNAc-targeting ligands connected to the nucleic acid via phosphate or thiophosphate linkages, using defined branching or bridging unit structures and formula-based ligand structures. Delivery is supported by conjugation to ligands, with cleavable linkers and optionally described liposome or lipoplex delivery formulations.
Claims Coverage
The independent claim set covers a TMPRSS6-inhibiting duplex nucleic acid defined by complementarity to TMPRSS6-transcribed RNA, a specified first-strand sequence, and chemical modification of one or both strands to form modified nucleotides. Additional inventive features include second-strand definition and modification mappings, terminal linkage and stabilization patterns, GalNAc ligand conjugation, and a lipid-based drug composition or formulation with defined lipid components and cationic lipid mol% range.
TMPRSS6-inhibiting duplex nucleic acid
A nucleic acid for inhibiting expression of TMPRSS6 comprising at least one duplex region with a first strand and a second strand that is at least partially complementary to the first strand, wherein the first strand is at least partially complementary to at least a portion of RNA transcribed from the TMPRSS6 gene.
Specific first-strand sequence with modified nucleotides
The nucleic acid comprises the first strand having 5′-3′: aaccagaagaagcagguga (SEQ ID NO: 333), wherein one or more nucleotides on the first strand are modified, or one or more nucleotides on the second strand are modified, or one or more nucleotides on the first strand and one or more nucleotides on the second strand are modified, to form modified nucleotides.
Second-strand definition with modification mappings
The nucleic acid further defines a first strand containing SEQ ID NO:17 and a second strand containing SEQ ID NO:18, where specific chemical modifications are defined by numbered mappings to modified nucleotides.
GalNAc ligand conjugate with a linker
The nucleic acid ligand comprises one or more N-acetyl galactosamine (GalNAc) moieties and derivatives connected to the nucleic acid via a linker.
Terminal phosphorothioate or phosphorodithioate linkage pattern
The connection between terminal 3′ and/or 5′ nucleotides of the first and/or second strand is phosphorothioate or phosphorodithioate.
Lipid-based drug composition with Atufect01-like cationic lipid system
A drug composition or formulation comprising the nucleic acid, or a conjugated nucleic acid, with a lipid-based delivery excipient comprising a cationic lipid, cholesterol, phosphatidylethanolamine, and a PEGylated lipid.
Cationic lipid mol% range within lipid formulation
The cationic lipid is present in a mol% range of about 55–65 mol%, preferably about 59 mol%.
Overall, the claim set covers TMPRSS6-inhibiting duplex nucleic acids with a defined first-strand sequence, modification of nucleotides on one or both strands, optional second-strand specification and modification mappings, and stabilization features using phosphorothioate or phosphorodithioate. Additional dependent features include GalNAc ligand conjugates with a linker and a lipid-based drug composition or formulation with defined lipid components and cationic lipid mol% range.
Stated Advantages
Inhibiting expression of TMPRSS6.
Treating anemia.
Ameliorating splenomegaly.
Reducing stressed erythropoiesis in the spleen.
Improving red blood cell maturation/erythropoiesis in the bone marrow.
Treatment and use for iron-overload related disorders and blood disorders, including hereditary hemochromatosis, β-thalassemias, sickle cell anaemia, congenital sideroblastic anemia, aplastic anemia, and myelodysplastic syndrome.
Increases hepcidin.
Reduces serum/plasma iron.
Reduces transferrin saturation.
Documented Applications
Therapeutic treatment of iron-overload related disorders and blood disorders, including hereditary hemochromatosis and blood disorders such as β-thalassemias, sickle cell anaemia, congenital sideroblastic anemia, aplastic anemia, and myelodysplastic syndrome.
Therapeutic treatment described for transfusional iron overload.
Treatment methods described for anemia and amelioration of splenomegaly with reduction of stressed erythropoiesis in the spleen and improved red blood cell maturation/erythropoiesis in the bone marrow.
Disease indications mentioned broadly in the provided content include Parkinson's Disease, Alzheimer's Disease, and Friedreich's Ataxia.
In vitro testing in human primary hepatocytes measuring TMPRSS6 mRNA reduction after dosing with GalNAc-siRNA.
In vitro evaluation of serum stability and receptor-mediated uptake for GalNAc-conjugated siRNA designs using different terminal/internal stabilization chemistries.
In vitro evaluation of alternate nucleoside/linker modifications for GalNAc-conjugated TMPRSS6-targeting siRNA.
Treatment of anemia.
Amelioration of splenomegaly.
Reduction of stressed erythropoiesis in the spleen.
Improvement of red blood cell maturation/erythropoiesis in the bone marrow.
Disorders associated with TMPRSS6/iron homeostasis, including hemochromatosis, porphyria cutanea tarda, β-thalassemia, sickle cell disease, congenital dyserythropoietic anemia, marrow failure syndromes, myelodysplasia, and transfusional iron overload.
Therapeutic use directed to neurodegenerative conditions when iron overload-associated, including Parkinson's Disease, Alzheimer's Disease, and Friedreich's Ataxia.
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