Modified Oligonucleotide Composition for miR-17 Targeting in PKD
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Solution Overview
Problem
Polycystic kidney disease (PKD) is characterized by the accumulation of fluid-filled cysts in the kidneys, leading to kidney enlargement and progressive loss of function, eventually resulting in end-stage renal disease, with existing treatments focusing on managing symptoms rather than addressing the underlying cyst growth.
Innovation Solution
A modified oligonucleotide comprising 9 linked nucleosides with specific sugar modifications and a nucleobase sequence is developed to inhibit the activity of the miR-17 family, which is upregulated in PKD, thereby reducing cyst growth and improving renal function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used to manage symptoms of PKD, then patient quality of life is maintained, but the underlying cyst growth and progression to end-stage renal disease is not addressed
Solution Approach 1:
The patent uses microRNA molecules as intermediaries to deliver the therapeutic effect. The antisense oligonucleotide binds to specific microRNA sequences (miR-17, miR-20a, miR-20b, miR-93, miR-106a, miR-106b) that are upregulated in PKD, thereby inhibiting their function and slowing cyst growth without directly targeting the cysts themselves
Solution Approach 2:
The patent replaces mechanical/surgical interventions with a molecular-level biochemical mechanism. Instead of physical removal or drainage of cysts, the treatment uses antisense oligonucleotides to modulate gene expression at the molecular level, addressing the root cause of cyst formation and growth
2Reliability
If antisense oligonucleotides are used to inhibit microRNA activity, then cyst growth is slowed, but the complexity of the molecular mechanism increases
Solution Approach 1:
The patent designs a single antisense oligonucleotide sequence that can target multiple microRNA molecules within the miR-17 family (miR-17, miR-20a, miR-20b, miR-93, miR-106a, miR-106b) that share common seed sequences. This multi-target approach simplifies the treatment mechanism while achieving comprehensive inhibition of cyst growth
Solution Approach 2:
The patent modifies the chemical parameters of the oligonucleotide by incorporating 2′-O-methyl and phosphorothioate modifications, which enhance stability and binding affinity. These parameter changes optimize the molecule's therapeutic effect while maintaining a relatively simple single-agent treatment approach
Data Source
AI summary
Provided herein are methods for the treatment of polycystic kidney disease, including autosomal dominant polycystic kidney disease, using modified oligonucleotides targeted to miR-17.