GH Variant and Antisense Oligonucleotide Combination for IGF-I Reduction
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Solution Overview
Problem
Current treatments for conditions associated with elevated insulin-like growth factor I (IGF-I) levels, such as acromegaly and cancers, are limited by the high cost, inconvenience, and side effects of existing GH variants like Somavert, which also fail to effectively reduce IGF-I levels in some patients.
Innovation Solution
A human growth hormone (GH) variant with specific amino acid substitutions (H18D, H21N, G120K, R167N, K168A, D171S, K172R, E174S, I179T) is combined with an antisense oligonucleotide targeted to the growth hormone receptor (GHR) to synergistically reduce IGF-I levels, offering a more effective and safer treatment option.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Somavert (GH variant) is used to reduce IGF-I levels, then IGF-I reduction is achieved, but cost increases and requires daily injection
Solution Approach 1:
The patent combines two mechanisms: GH variant (proteinsomatomedin C) that blocks GH receptor and antisense oligonucleotide that degrades GHR mRNA. This combination achieves superior IGF-I reduction compared to Somavert monotherapy while the oligonucleotide's longer half-life reduces the need for daily injections.
Solution Approach 2:
The antisense oligonucleotide acts as an intermediary that degrades GHR mRNA, preventing GH receptor formation. This provides an additional layer of control over the GH/IGF-I axis beyond direct GH receptor blocking, enhancing therapeutic efficacy.
2Reliability
If Somavert dose is escalated to reduce IGF-I levels, then IGF-I reduction improves, but side effects increase
Solution Approach 1:
The combination of GH variant and antisense oligonucleotide provides synergistic IGF-I reduction. The oligonucleotide's mechanism of degrading GHR mRNA complements the GH variant's receptor blocking, achieving better efficacy at lower doses and reducing dose-related side effects.
Solution Approach 2:
The patent changes the therapeutic approach from purely protein-based (GH variant) to a combination including nucleic acid-based (antisense oligonucleotide) therapy. This parameter change in therapy composition enables more effective IGF-I reduction with improved safety profile.
3Reliability
If combination therapy with SST agonist is used, then tumor size reduction is achieved, but cost and complexity increase
Solution Approach 1:
The patent merges GH variant with antisense oligonucleotide targeting GHR, creating a combination that achieves superior IGF-I reduction. This combination approach, while more complex than monotherapy, provides enhanced efficacy for conditions like acromegaly and IGF-I-dependent cancers.
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 combination of the GH variant and antisense oligonucleotide exhibits a greater than additive effect in reducing serum/plasma IGF-I levels, providing a potentially more effective treatment for conditions like acromegaly, diabetic retinopathy, diabetic nephropathy, and IGF-I positive cancers with reduced side effects and improved convenience compared to existing therapies.
Implementation Method 1
an oligonucleotide 15 to 30 nucleobases in length comprising at least one modified internucleoside linkage, sugar moiety, or nucleobase, targeted to a nucleic acid encoding human growth hormone receptor (GHR) so as to inhibit expression of the GHR
Implementation Method 2
Growth hormone signaling is mediated by this interaction. Growth hormone signaling causes the production of another hormone, insulin-like growth factor I (IGF-I)
Data Source
AI summary
The present disclosure relates to a method for treatment or prevention of diseases have an increased level of insulin-like growth factor I (IGF-I). The method comprises administration of a growth hormone (GH) variant having antagonistic activity in combination with an oligonucleotide targeted to growth hormone receptor (GHR) to a subject in need.