Chimeric Aptamer Construct for Dual PDGF and VEGF Inhibition
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Solution Overview
Problem
Current treatments for proliferative disorders such as atherosclerosis, macular degeneration, and cancer, which involve PDGF and VEGF, often require dual inhibition of these growth factors for effective blocking of angiogenesis, but existing therapies may not fully inhibit ocular angiogenesis and have limitations in efficacy and stability.
Innovation Solution
Development of aptamers that bind specifically to PDGF-B and VEGF, including their isoforms, with modified nucleic acid sequences featuring phosphorothioate linkages and 2'-O-methyl modifications, allowing for simultaneous or independent binding to these growth factors, thereby inhibiting their signaling pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies are used to inhibit PDGF and VEGF, then some blocking of angiogenesis is achieved, but the inhibition is not sufficient and ocular angiogenesis is not fully blocked
Solution Approach 1:
The patent combines two separate aptamers into a single chimeric aptamer construct that can bind both PDGF and VEGF simultaneously. This merging of functions into one molecule achieves dual inhibition of both growth factors, resolving the contradiction by providing more complete angiogenesis blocking while maintaining therapeutic reliability.
Solution Approach 2:
The chimeric aptamer is designed to perform multiple functions: binding to PDGF, binding to VEGF, and inhibiting both signaling pathways. This multi-functional design allows a single therapeutic agent to achieve comprehensive angiogenesis inhibition, addressing the insufficiency of conventional single-target therapies.
2Reliability
If aptamers with modified nucleic acid sequences are developed, then binding affinity and stability are enhanced, but the complexity of the molecule increases
Solution Approach 1:
The patent applies parameter changes by modifying the nucleic acid sequence at specific positions (introducing phosphorothioate linkages and 2'-O-methyl modifications) to enhance stability and binding affinity. These targeted parameter changes improve molecular properties without requiring complete redesign of the entire aptamer structure, thus managing complexity while achieving enhanced reliability.
3Reliability
If dual inhibition of PDGF and VEGF is implemented, then more effective blocking of angiogenesis is achieved, but the therapeutic regimen becomes more complex
Solution Approach 1:
The patent merges the functions of two separate therapeutic agents (PDGF aptamer and VEGF aptamer) into a single chimeric aptamer molecule. This consolidation achieves dual inhibition of both growth factors while simplifying the therapeutic regimen from multiple administrations to a single therapeutic intervention, resolving the contradiction between efficacy and complexity.
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 aptamers demonstrate enhanced binding affinity and stability, leading to improved inhibition of PDGF and VEGF-mediated processes, resulting in more effective treatment outcomes for conditions like wet AMD, with increased visual acuity benefits and neovascular regression.
Implementation Method 1
aptamers that bind specifically to PDGF-B and VEGF, including their isoforms
Implementation Method 2
modified nucleic acid sequences featuring phosphorothioate linkages and 2'-O-methyl modifications
Data Source
Figure 1A~1B
Figure 1C~1D
Figure 2A
AI summary
Aptamers having improved stability against nucleases that bind PDGF and aptamers that bind VEGF are provided. In addition, aptamer constructs comprising a PDGF aptamer and a VEGF aptamer are provided. Pharmaceutical compositions comprising the aptamers and aptamer constructs are provided, as well as methods of treating conditions using the aptamers and aptamer constructs.