PKD1 Antisense Oligonucleotides for ADPKD Cyst Growth Reduction
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is an ongoing need for new treatments or preventative measures for Autosomal Dominant Polycystic Kidney Disease (ADPKD), a progressive disorder characterized by the growth of kidney cysts due to reduced Polycystin 1 function, which leads to significant morbidity and reduced life expectancy.
Innovation Solution
The use of antisense oligonucleotides (ASOs) and antisense RNA (AR) compositions that modulate the post-transcriptional or translational regulation of the 3′ untranslated region (UTR) of PKD1 mRNA, blocking specific binding of miR-17 and miR-200 family miRNAs to increase Polycystin 1 protein levels, thereby reducing kidney cyst growth.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for ADPKD, then disease progression is managed, but Polycystin 1 function remains insufficient leading to continued cyst growth
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that bind to miRNA to prevent them from binding to PKD1 mRNA. This intermediary approach blocks the harmful miRNA-PKD1 interaction, thereby increasing Polycystin 1 function and reducing cyst growth without directly modifying the protein itself
Solution Approach 2:
The invention changes the molecular interaction parameters by introducing ASOs that alter the binding affinity between miRNA and PKD1 mRNA. By modifying this molecular parameter (blocking the binding), the system achieves increased Polycystin 1 function and reduced cystogenesis
2Quantity of substance
If miRNA binding to PKD1 3′ UTR is blocked, then Polycystin 1 protein levels increase, but the mechanism requires specific molecular targeting
Solution Approach 1:
Antisense oligonucleotides serve as mediators that indirectly increase Polycystin 1 levels by blocking miRNA binding. This intermediary mechanism avoids the complexity of directly delivering or expressing the Polycystin 1 protein, instead using a simpler nucleic acid-based approach to achieve the same functional outcome
Solution Approach 2:
The patent uses antisense sequences that are complementary copies of the miRNA binding site on PKD1 mRNA. These antisense copies act as decoys or blockers, preventing the actual miRNA from binding to the target mRNA, thereby indirectly increasing Polycystin 1 expression without complex protein delivery systems
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 ASOs and ARs effectively increase Polycystin 1 protein levels, leading to reduced kidney cyst growth and size in 3D kidney cyst cultures, providing a potential therapeutic approach for ADPKD.
Implementation Method 1
an ASO that binds to a targeted portion of the 3′ UTR of a PKD1 mRNA, wherein binding of the antisense oligonucleotide to the targeted portion increases the level of Polycystin 1 protein
Data Source
AI summary
Described herein are antisense oligonucleotides, vectors, and related compositions and methods for increasing expression of PKD1 mRNA and Polycystin 1 protein and uses thereof for the treatment of autosomal dominant polycystic kidney disease (ADPKD).