Methods for safely reducing thrombopoietin
Inventors
Gruber, Andras • Tucker, Erik • Monia, Brett P. • Revenko, Alexey
Assignees
ARONORA Inc • Oregon Health and Science University • Ionis Pharmaceuticals Inc
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Publication Number
US-12496311-B2
Publication Date
2025-12-16
Expiration Date
Abstract
Provided herein are methods, compounds, and compositions for safely reducing thrombopoietin in a cell or an individual. Such methods, compounds, and compositions maintain platelet count within a safe hemostatic range. Such methods, compounds, and compositions are useful to safely treat, prevent, or ameliorate a disease that can benefit from platelet count reduction in an individual. Such methods, compounds, and compositions are useful for treating or preventing diseases in which thrombopoietin contributes to the presence or activation of platelets contributes to and promotes disease initiation or progression, and/or adversely affects disease outcome.
Core Innovation
The invention relates to modified antisense oligonucleotides targeting thrombopoietin (TPO) mRNA, including modified morpholinos with acyclic moieties and bicyclic sugar surrogates. The disclosed oligonucleotides include selectable modified nucleobases, including 5-methylcytosine, and modified internucleoside linkages, including phosphorothioate internucleoside linkages.
The disclosure includes oligonucleotide motif architectures, including a gapmer motif with wing region and gap region differences, including a deoxy gapmer configuration. The wing and gap regions incorporate specified modified sugar and linkage selections, including patterns, blocks, and quantity considerations for phosphorothioate linkages, in relation to nuclease resistance.
The invention further includes conjugate moieties and conjugate linkers for attaching the modified oligonucleotide to a cell-targeting ligand. The disclosure includes GalNAc-based conjugates, including “LICA-1,” and optional cleavable moieties within the conjugate linker, including cleavable phosphate/phosphodiester bonds and linker-nucleosides. Therapeutic use is described in connection with TPO mRNA knockdown and downstream platelet count reduction, with further biological outcomes described in mouse breast cancer models.
Claims Coverage
The independent claim family centers on administering a compound comprising a modified oligonucleotide targeting TPO mRNA for treatment of breast cancer and/or myeloproliferative neoplasms where TPO or platelet activity contributes to initiation or progression. The claim refinements add structural selections, platelet-count constraints, patient-selection ranges, and concomitant or consecutive additional therapy.
Method of treating cancers with modified oligonucleotides targeting TPO mRNA
Administering a compound comprising a modified oligonucleotide targeting TPO mRNA to an individual, thereby treating breast cancer, myeloproliferative neoplasms, or combination thereof in the individual wherein thrombopoietin (TPO) or platelet activity contributes to initiation or progression.
Gap- and wing-structured modified oligonucleotide with modified sugars
A modified oligonucleotide includes an adjacent gap segment flanked by 5′ and 3′ wing segments, with each nucleoside in the wing segments containing a modified sugar.
Specified modified linkage, sugar, and nucleobase selections
The modified internucleoside linkage is a phosphorothioate linkage, the modified sugar is either a bicyclic sugar or 2′-O-methoxyethyl, and the modified nucleobase is 5-methylcytosine.
Platelet count partial reduction with hemostatically safe TPO maintenance
Administering a compound that partially reduces an individual’s platelet count without reducing it below about 25,000/μL, while leaving enough synthesis of TPO to maintain a hemostatically safe platelet count.
Pre-treatment platelet count range limitation
Applying the method to an individual whose platelet count is within about 100,000/μL to about 2,000,000/μL prior to administering the compound.
Concomitant or consecutive administration with an additional therapy
Administering the compound and at least one additional therapy concomitantly or consecutively.
The core coverage centers on administering a modified oligonucleotide targeting TPO mRNA for treatment of breast cancer and/or myeloproliferative neoplasms where TPO or platelet activity contributes to initiation or progression, with specified structural selections and treatment parameters.
Stated Advantages
Treating breast cancer and/or myeloproliferative neoplasms where TPO or platelet activity contributes to initiation or progression.
Partially reducing platelet count while maintaining a hemostatically safe platelet count.
Partially reduces platelet count while leaving enough synthesis of TPO to maintain a hemostatically safe platelet count.
Documented Applications
Method of treating breast cancer in an individual where thrombopoietin (TPO) or platelet activity contributes to initiation or progression.
Method of treating myeloproliferative neoplasms in an individual where thrombopoietin (TPO) or platelet activity contributes to initiation or progression.
Method of treating a combination of breast cancer and myeloproliferative neoplasms in an individual where TPO or platelet activity contributes to initiation or progression.
TPO mRNA knockdown and platelet count reduction, including described effects in mouse breast cancer models (tumor burden/metastasis, including pulmonary metastasis).
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