Antisense oligonucleotide modulators of serotonin receptor 2C and uses thereof
Inventors
Stamm, Stefan • Shen, Manli • Josiah, Serene
Assignees
Takeda Pharmaceutical Co Ltd • University of Kentucky
Publication Number
US-9567585-B2
Publication Date
2017-02-14
Expiration Date
2032-11-09
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Abstract
The present invention provides, among other things, oligonucleotide modulators of human 5′-HT2C receptor (HTR2C) and improved methods and composition for treating HTR2C-related diseases, disorders or conditions based on such modulators. In particular, oligonucleotides modulators according to the invention target specific regions in the Exon V/Intron V junction of the human HTR2C pre-mRNA and drive expression of HTR2C Vb splice isoform, leading to increased generation of non-edited strong HTR2C receptor and enhanced serotonin receptor activity.
Core Innovation
The invention provides antisense oligonucleotide modulators that specifically target the Exon V/Intron V junction of the human 5′-HT2C receptor (HTR2C) pre-mRNA. These oligonucleotide modulators promote inclusion of Exon Vb, resulting in increased generation of the HTR2C Vb splice isoform and, consequently, higher expression of the strong, non-edited serotonin receptor and enhanced serotonin receptor activity. The invention covers both the oligonucleotide compositions and their use in treating HTR2C-related diseases, disorders, or conditions.
The problem addressed by this invention is the limitation of current pharmaceutical HTR2C agonists, such as fenfluramine-phentermine and locaserin, which act by targeting the HTR2C protein directly and are ineffective where the HTR2C protein is reduced or absent, such as in Prader-Willi Syndrome (PWS). There is also a broader need for more effective treatments for obesity and other HTR2C-related disorders given the global prevalence and health risks associated with obesity, as well as the side effects of existing therapies.
The core innovation utilizes short antisense oligonucleotides (for example, an 18-mer antisense RNA) that bind under stringent conditions to specific regions at the Exon V/Intron V junction of HTR2C pre-mRNA. These molecules enhance the production of the HTR2C Vb isoform, increasing levels of the highly active, non-edited 5-HT2C receptor. Such oligonucleotides can modulate receptor activity in vitro and in vivo, and have demonstrated efficacy in promoting anorexic responses and reducing food intake when delivered to relevant brain regions.
Methods and compositions described include antisense oligonucleotides 10-50 nucleotides in length, with a sequence permitting specific hybridization to target regions of the HTR2C pre-mRNA, optionally with chemical modifications for increased stability. The invention also comprises pharmaceutical compositions, kits, and therapeutic methods for modulating HTR2C activity or treating diseases associated with HTR2C dysfunction, such as hyperphagia, obesity, and Prader-Willi Syndrome, by administration of the described antisense oligonucleotides.
Claims Coverage
The patent claims cover five main inventive features relating to antisense oligonucleotide modulators targeting the human 5′-HT2C receptor (HTR2C) pre-mRNA, their compositions, and their therapeutic uses.
Antisense oligonucleotide targeting the HTR2C pre-mRNA under stringent conditions
An antisense oligonucleotide of 16-50 nucleotides in length comprising a sequence that permits specific hybridization to a target region of a human 5′-HT2C receptor (HTR2C) pre-mRNA under stringent conditions. The target region may include nucleotides corresponding to specific sequences defined within SEQ ID NO:1.
Pharmaceutical composition comprising antisense oligonucleotide and pharmaceutically acceptable carrier
A pharmaceutical composition comprising the antisense oligonucleotide capable of hybridizing to the HTR2C pre-mRNA as claimed, blended with a pharmaceutically acceptable carrier.
Kit comprising antisense oligonucleotide and tools for brain administration
A kit containing the antisense oligonucleotide described and tools for administration to the brain of a mammal.
Antisense oligonucleotide with chemical modifications
An antisense oligonucleotide, no more than 50 nucleotides long, comprising a sequence for specific hybridization to a target region of HTR2C pre-mRNA, selected from specified sequences, and having a ribose group modified with a methyl group, wherein the oligonucleotide, once delivered, modulates HTR2C activity.
Methods of modulating HTR2C activity and treating related conditions
Methods including: delivering the antisense oligonucleotide to a cell to modulate HTR2C activity; administration to neurons or the hypothalamus; reducing food consumption in a subject; and treating hyperphagia, obesity, and Prader-Willi Syndrome by administration of the antisense oligonucleotide.
In summary, the claims encompass antisense oligonucleotides targeting the HTR2C pre-mRNA under stringent conditions, their pharmaceutical formulations, medical kits, chemically modified versions, and methods for their therapeutic use in modulating HTR2C activity and treating HTR2C-related disorders.
Stated Advantages
Antisense oligonucleotides targeting the HTR2C pre-mRNA can effectively promote expression of the HTR2C Vb isoform, leading to increased levels of the strongest serotonin receptor and enhanced receptor activity.
These modulators provide a method to treat HTR2C-related diseases, disorders, or conditions, including cases where the HTR2C protein is reduced or absent, such as in Prader-Willi Syndrome, which are not treatable by existing HTR2C agonists.
Short antisense oligonucleotides are effective both in vitro and in vivo, require only nanomolar concentrations, and can be efficiently delivered to relevant neurons to elicit physiological effects, such as reduction in food intake.
Documented Applications
Treatment of hyperphagia by administering an antisense oligonucleotide targeting the HTR2C pre-mRNA to a subject in need.
Treatment of obesity by administering an antisense oligonucleotide targeting the HTR2C pre-mRNA to a subject in need.
Treatment of Prader-Willi Syndrome by administering an antisense oligonucleotide targeting the HTR2C pre-mRNA to a subject in need.
Reduction of food consumption in subjects via administration of the described antisense oligonucleotide.
Modulation of human 5′-HT2C receptor (HTR2C) activity in cells, including neurons and neurons specific to the hypothalamus region of the brain.
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