Modified TGF-beta Oligonucleotide for Glaucoma Bleb Maintenance
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for ophthalmic diseases such as wet age-related macular degeneration, glaucoma, and diabetic retinopathy are limited in effectiveness, particularly for patients who do not respond to standard medications or undergo trabeculectomy, as they face issues with scarring, intraocular pressure, and optic nerve damage.
Innovation Solution
A TGF-beta oligonucleotide with a nucleic acid sequence of GACCAGATGCAGGA, modified at the 3′-end and/or 5′-end with 1 to 4 nucleotides, is used alone or in combination with active agents to inhibit scarring, epithelial-to-mesenchymal transition, and reduce intraocular pressure, thereby addressing key pathophysiologic steps in glaucoma progression and post-trabeculectomy alterations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard medications or conventional treatments are used for ophthalmic diseases, then treatment is simple and cost-effective, but effectiveness is limited particularly for patients who do not respond to standard medications
Solution Approach 1:
The patent applies parameter changes by modifying the oligonucleotide structure with specific chemical groups (phosphorothioate backbone, LNA modifications) to enhance stability and binding affinity. This resolves the contradiction by changing the molecular parameters of the treatment agent to achieve superior effectiveness for refractory cases while maintaining a targeted molecular approach rather than complex multi-component systems
Solution Approach 2:
The patent uses composite materials by combining multiple modification types (phosphorothioate backbone modification plus LNA nucleotide modifications) within a single oligonucleotide molecule. This composite structure achieves enhanced effectiveness for difficult-to-treat cases while maintaining the simplicity of a single molecular entity rather than requiring complex combination therapies
2Stress or pressure
If trabeculectomy surgery is performed to reduce intraocular pressure, then intraocular pressure control is improved, but scarring and fibrotic closure occur reducing long-term effectiveness
Solution Approach 1:
The patent applies preliminary anti-action by administering the antisense oligonucleotide before or during trabeculectomy surgery to preemptively inhibit TGF-beta2 expression. This prevents the fibrotic scarring process before it can compromise the surgical outcome, thereby maintaining intraocular pressure control effectiveness over the long term by counteracting the natural fibrotic response that would otherwise reduce surgical durability
Solution Approach 2:
The patent converts the harmful fibrotic response (TGF-beta2-mediated scarring) into a beneficial therapeutic target. By specifically inhibiting TGF-beta2 with the modified oligonucleotide, the treatment transforms the pathological fibrotic process into a controlled therapeutic intervention that prevents bleb closure while maintaining the desired intraocular pressure reduction, effectively turning the disease mechanism against itself
3Reliability
If TGF-beta2 expression is inhibited to prevent scarring, then fibrotic closure is reduced, but the mechanism requires complex modified oligonucleotides
Solution Approach 1:
The patent applies parameter changes by systematically modifying the oligonucleotide's chemical parameters (backbone phosphorothioate substitution, LNA nucleotide incorporation at specific positions) to achieve optimal stability and affinity for TGF-beta2 mRNA. These parameter changes resolve the contradiction by creating a molecule with enhanced therapeutic reliability while maintaining a defined, manufacturable structure rather than requiring overly complex or undefined molecular architectures
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 oligonucleotide effectively reduces scarring, maintains bleb size, and lowers intraocular pressure persistently, providing long-lasting antifibrotic and anti-angiogenic effects, thereby improving treatment outcomes for advanced ophthalmic diseases.
Implementation Method 1
RNase H is an ubiquitous enzyme that hydrolyzes the RNA strand of an RNA/DNA duplex
Implementation Method 2
RNase H is an ubiquitous enzyme that hydrolyzes the RNA strand of an RNA/DNA duplex
Implementation Method 3
a wide range of chemical modifications have been explored and implemented over the years
Data Source
AI summary
The present invention is directed to an oligonucleotide comprising a nucleic acid sequence of SEQ ID No. 1 or parts thereof, wherein 1 to 4 nucleotides at the 3′-end and/or at the 5′-end of the oligonucleotide are modified at a base, a sugar and/or a phosphate for use in a method of reducing or inhibiting of scarring, of fibrotic closure of the trabeculectomy canal, of epithelial-to-mesenchymal transition of the trabecular meshwork and/or providing of protecting activity of the optic nerve optionally the optic nerve head. Further, the present invention refers to a pharmaceutical composition comprising such oligonucleotide and a pharmaceutically acceptable carrier.