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PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates
Marie W Lindholm1, Joacim Elmén, Niels Fisker
1Santaris Pharma A/S, Hørsholm, Denmark. mwl@santaris.com
Abstract:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for the reduction of low-density lipoprotein cholesterol (LDL-C). PCSK9 increases the degradation of the LDL receptor, resulting in high LDL-C in individuals with high PCSK9 activity. Here, we show that two locked nucleic acid (LNA) antisense oligonucleotides targeting PCSK9 produce sustained reduction of LDL-C in nonhuman primates after a loading dose (20 mg/kg) and four weekly maintenance doses (5 mg/kg). PCSK9 messenger RNA (mRNA) and serum PCSK9 protein were reduced by 85% which resulted in a 50% reduction in circulating LDL-C. Serum total cholesterol (TC) levels were reduced to the same extent as LDL-C with no reduction in high-density lipoprotein levels, demonstrating a specific pharmacological effect on LDL-C. The reduction in hepatic PCSK9 mRNA correlated with liver LNA oligonucleotide content. This verified that anti-PCSK9 LNA oligonucleotides regulated LDL-C through an antisense mechanism. The compounds were well tolerated with no observed effects on toxicological parameters (liver and kidney histology, alanine aminotransferase, aspartate aminotransferase, urea, and creatinine). The pharmacologic evidence and initial safety profile of the compounds used in this study indicate that LNA antisense oligonucleotides targeting PCSK9 provide a viable therapeutic strategy and are potential complements to statins in managing high LDL-C.
Insights
Locked nucleic acid (LNA) antisense oligonucleotides targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) effectively lowered LDL-C in nonhuman primates. This indicates a promising new therapeutic strategy for managing high cholesterol levels.
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein cholesterol (LDL-C) metabolism.
- Elevated PCSK9 activity leads to increased LDL-C levels, contributing to cardiovascular disease risk.
- Targeting PCSK9 offers a therapeutic strategy for hypercholesterolemia.
Purpose of the Study:
- To evaluate the efficacy and safety of locked nucleic acid (LNA) antisense oligonucleotides targeting PCSK9 in nonhuman primates.
- To confirm the antisense mechanism of action for PCSK9 inhibition by LNA oligonucleotides.
- To assess the potential of LNA-based PCSK9 inhibitors as a complementary therapy to statins.
Main Methods:
- Administration of LNA antisense oligonucleotides targeting PCSK9 to nonhuman primates.
- Measurement of PCSK9 messenger RNA (mRNA) and protein levels in serum and liver.
- Quantification of serum lipid profiles, including LDL-C and total cholesterol (TC).
- Toxicological assessment of liver and kidney function and histology.
Main Results:
- Sustained reduction in circulating LDL-C by approximately 50% following LNA oligonucleotide treatment.
- Significant reduction (around 85%) in both PCSK9 mRNA and serum PCSK9 protein levels.
- Demonstrated specific pharmacological effect on LDL-C with no impact on high-density lipoprotein levels.
- Correlated reduction in hepatic PCSK9 mRNA with liver LNA oligonucleotide content, confirming antisense mechanism.
- Compounds were well-tolerated with no observed adverse effects on key toxicological parameters.
Conclusions:
- LNA antisense oligonucleotides targeting PCSK9 effectively and safely reduce LDL-C in nonhuman primates.
- The observed effects confirm an antisense mechanism of action for PCSK9 regulation.
- These LNA oligonucleotides represent a viable therapeutic strategy for managing high LDL-C and may complement statin therapy.
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