PCSK9 Antisense Oligomer Gapmers for Reduced Kidney Toxicity
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Solution Overview
Problem
Existing PCSK9 targeting antisense compounds face issues with toxicity, particularly kidney toxicity, while maintaining efficacy similar to SPC5001, which is a potent inhibitor of PCSK9.
Innovation Solution
Development of new human PCSK9 sequences and longer variants of SPC5001 sequences with reduced toxicity, combined with conjugates that enhance therapeutic index, forming antisense oligonucleotides with specific lengths and nucleotide analogues like LNA, and conjugates such as cholesterol or GalNAc, linked via biocleavable linkers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If LNA antisense oligonucleotides are used to target PCSK9, then PCSK9 inhibition efficacy is improved, but kidney toxicity increases
Solution Approach 1:
The patent applies parameter changes by modifying the oligonucleotide structure from standard LNA to LNA gapmer with specific DNA/RNA ratios (e.g., 4-6 DNA nucleotides flanking a central RNA region). This structural parameter change reduces kidney toxicity while preserving PCSK9 inhibition efficacy, as the gapmer configuration alters cellular uptake and processing pathways.
Solution Approach 2:
The invention uses composite materials by creating LNA gapmer oligonucleotides that combine different nucleotide types (LNA, DNA, and RNA segments) in a single molecule. This composite structure leverages the high affinity of LNA for target binding while the DNA/RNA components modulate toxicity profiles, achieving both efficacy and safety.
2Power
If LNA oligonucleotides are used to target PCSK9, then potency is improved, but hepatotoxicity increases
Solution Approach 1:
The patent applies parameter changes by adjusting the oligonucleotide length to 14-16 nucleotides and modifying the LNA-to-DNA ratio in the gapmer structure. These parameter adjustments reduce hepatotoxicity while maintaining potency, as the optimized length and composition reduce off-target effects and improve metabolic stability in the liver.
Solution Approach 2:
The invention employs shorter oligonucleotide sequences (14-16 nt) compared to longer traditional antisense oligos. These shorter sequences achieve sufficient target binding affinity while reducing cumulative toxicity burden, effectively using minimal necessary length to achieve therapeutic effect.
3Object-affected harmful factors
If short LNA gapmers (12-14 nt) are used, then hepatotoxicity is reduced, but PCSK9 inhibition efficacy may be compromised
Solution Approach 1:
The patent applies parameter changes by optimizing the gapmer structure with specific configurations: 4-6 DNA nucleotides at the 5' end, a central RNA region (2-4 nucleotides), and 4-6 DNA nucleotides at the 3' end. This specific parameter configuration ensures that even at 14-16 total nucleotides, the oligonucleotide maintains sufficient binding affinity for PCSK9 mRNA while reducing hepatotoxicity.
Solution Approach 2:
The invention uses composite materials by creating LNA gapmer oligonucleotides that combine different nucleotide types (LNA, DNA, and RNA segments) in a single molecule. This composite structure leverages the high affinity of LNA for target binding while the DNA/RNA components modulate toxicity profiles, achieving both efficacy and safety.
Data Source
AI summary
The present invention relates to oligomeric compounds and conjugates thereof that target Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) PCSK9 mRNA in a cell, leading to reduced expression of PCSK9. Reduction of PCSK9 expression is beneficial for a range of medical disorders, such as hypercholesterolemia and related disorders.