Antisense Oligonucleotides Modulate HTR2C Receptor Splicing

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Solution Overview

Problem

Current treatments for obesity and related conditions, such as Prader-Willi Syndrome, are inadequate due to the limitations of existing pharmaceutical HTR2C agonists that fail to effectively target the 5-HT2C receptor, particularly in cases where the receptor is dramatically reduced or absent, leading to side effects and inefficacy in managing hyperphagia and obesity.

Innovation Solution

Development of short antisense oligonucleotides that specifically target the Exon V/Intron V junction of the human HTR2C pre-mRNA to promote the expression of the HTR2C Vb isoform, enhancing serotonin receptor activity and reducing food intake by administering these oligonucleotides directly to the brain, thereby modulating HTR2C activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If traditional HTR2C agonists (fen-phen, lorcaserin) are used to treat obesity, then weight loss is achieved, but side effects occur (pulmonary hypertension, heart valve damage) and they are ineffective when HTR2C receptor is reduced or absent

Engineering Contradiction:

Improveeffectiveness of HTR2C agonistsVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

Instead of using agonists to activate the HTR2C receptor, the patent uses antisense oligonucleotides to increase the expression of the HTR2C Vb isoform, which is the functional receptor form. This inverse approach addresses cases where receptor expression is reduced or absent, and avoids the side effects associated with traditional agonists that target multiple serotonin receptors.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent employs short antisense oligonucleotides (10-50 nucleotides) that specifically target the Exon V/Intron V junction of HTR2C pre-mRNA to promote Vb isoform expression. This localized molecular intervention increases the proportion of functional HTR2C receptors without affecting other serotonin receptor subtypes, thereby achieving weight loss without the cardiovascular side effects of traditional agonists.

Inventive Principle:

Principle #3Local quality

2Reliability

If HTR2C agonists are administered to treat Prader-Willi Syndrome, then hyperphagia is targeted, but treatment fails because HTR2C protein is dramatically reduced or absent

Engineering Contradiction:

Improveeffectiveness in Prader-Willi SyndromeVSAvoidapplicability to HTR2C-deficient conditions

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent administers antisense oligonucleotides before they are needed to activate the receptor, as these oligonucleotides work by increasing the expression of HTR2C Vb isoform from pre-mRNA. This preliminary action of upregulating receptor expression addresses the underlying deficiency in Prader-Willi Syndrome, making the treatment effective even when baseline HTR2C protein levels are dramatically reduced or absent.

Inventive Principle:

Principle #10Preliminary action

3Measurement precision

If long antisense oligonucleotides are used to target HTR2C pre-mRNA, then specificity is achieved, but delivery to the brain and cellular uptake are hindered

Engineering Contradiction:

Improvespecificity of target bindingVSAvoiddelivery to brain and cellular uptake

Core Design Contradiction:

Measurement precisionVSEase of operation

Solution Approach 1:

The patent divides the antisense oligonucleotide into a short sequence of 10-50 nucleotides that specifically targets the Exon V/Intron V junction of HTR2C pre-mRNA. This segmented, compact design maintains binding specificity while dramatically improving delivery to the brain and cellular uptake compared to longer oligonucleotides, as the short sequence can more efficiently cross the blood-brain barrier and enter neurons.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent uses a partial sequence (10-50 nucleotides) of the full antisense oligonucleotide that is sufficient to achieve specific binding to the Exon V/Intron V junction. This partial action approach provides adequate specificity while optimizing delivery properties, as the shorter sequence requires less energy for transport and exhibits better pharmacokinetic properties in the central nervous system.

Inventive Principle:

Principle #16Partial or excessive action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The antisense oligonucleotides effectively increase the expression of the HTR2C Vb isoform, leading to reduced food consumption and potential treatment of obesity, hyperphagia, and Prader-Willi Syndrome by enhancing serotonin receptor activity, providing a more targeted and effective approach compared to traditional agonists.

Implementation Method 1

comprising a sequence that permits specific hybridization to a target region of a human 5′-HT2C receptor (HTR2C) pre-mRNA

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentUS10415039B2Antisense oligonucleotide modulators of serotonin receptor 2C and uses thereof

Publication Date: 2019.09.17 TAKEDA PHARMA CO LTD

AI summary

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.