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Publication Number
US-12134772-B2
Publication Date
2024-11-05
Expiration Date
Abstract
The present disclosure relates to compositions and methods for modulating gene expression and in particular to compositions and methods for increasing expression of Klotho. In certain examples, the present disclosure provides a method of increasing expression of a Klotho gene in a cell the method comprising administering to the cell a binding molecule that binds to an RNA transcript transcribed from a chromosomal region within or near the Klotho gene, wherein the RNA transcript does not encode a Klotho protein.
Core Innovation
The disclosure describes increasing expression of a Klotho gene in a cell or in a subject by administering a nucleic acid that hybridizes to an RNA transcript transcribed from a chromosomal region within or near the Klotho gene. The RNA transcript targeted for hybridization does not encode a Klotho protein. The nucleic acid is between about 15 and 50 nucleotides in length and comprises a region of at least 15 nucleotides that is substantially complementary to the RNA transcript.
A key aspect of the disclosed approach is the selection of the chromosomal region from which the noncoding RNA transcript is transcribed, specifically within or near the Klotho gene. The chromosomal region is defined relative to Klotho gene translation start and translation stop sites, including ranges described as quantitative spans upstream and downstream. The disclosure further characterizes target RNA transcript types, including sense RNA transcript and antisense RNA transcript.
The disclosure also defines sequence-based constraints for both the RNA transcript and the administered nucleic acid. The RNA transcript is specified as containing the sequence of a listed SEQ ID NO or a sequence at least about 90% identical to the listed SEQ ID NO. The administered nucleic acid can include a sequence that is at least about 90% identical to one of several listed SEQ IDs, and substantially complementary hybridization is maintained within the specified length constraints.
Claims Coverage
The independent claims cover three method categories: increasing Klotho gene expression in a cell, treating specified disorders, and enhancing cognition. Across the independent claims, the main inventive features are the target RNA transcript source region within or near the Klotho gene, the short length and substantial complementarity requirements, and the increase in Klotho gene expression after administration, with dependent claims adding positional windows and sequence identity and composition constraints.
Hybridizing nucleic acid targeting a non-Klotho-encoding RNA transcript from a Klotho chromosomal region
A method of increasing expression of a Klotho gene in a cell by administering a nucleic acid that hybridizes to an RNA transcript transcribed from a chromosomal region within or near the Klotho gene, wherein the RNA transcript does not encode a Klotho protein.
15–50 nucleotide nucleic acid with at least 15 nucleotides substantially complementary
The nucleic acid is between about 15 and 50 nucleotides in length and comprises a region of at least 15 nucleotides that is substantially complementary to the RNA transcript.
Therapeutic administration increasing Klotho gene expression for specified disorders
A method of treating cancer, a muscle disorder, a kidney disorder, or neurological disorder by administering to the subject a therapeutically effective amount of a nucleic acid that hybridizes to an RNA transcript transcribed from a chromosomal region within or near a Klotho gene, wherein the RNA transcript does not encode a Klotho protein, and wherein administration increases expression of the Klotho gene in the subject.
Cognition enhancement by increasing Klotho gene expression
A method of enhancing cognition in a subject having a neurological disorder by administering to the subject a therapeutically effective amount of a nucleic acid that hybridizes to an RNA transcript transcribed from a chromosomal region within or near a Klotho gene, wherein the RNA transcript does not encode a Klotho protein, and wherein administration increases expression of the Klotho gene in the subject.
Across the independent claims, the disclosed inventive coverage centers on administering a short nucleic acid that is substantially complementary to an RNA transcript transcribed from a chromosomal region within or near the Klotho gene, where the RNA transcript does not encode a Klotho protein, and wherein administration increases expression of the Klotho gene for cell expression enhancement, treatment of specified disorders, and enhancing cognition in a neurological disorder subject.
Stated Advantages
Increases expression of the Klotho gene in the cell or subject.
Treatment of cancer, a muscle disorder, a kidney disorder, or neurological disorder.
Enhancing cognition in a subject having a neurological disorder.
Documented Applications
Treating cancer, a muscle disorder, a kidney disorder, or neurological disorder in a subject by administering a therapeutically effective amount of the hybridizing nucleic acid.
Enhancing cognition in a subject having a neurological disorder by administering a therapeutically effective amount of the hybridizing nucleic acid.
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