Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics

Area of Science:

• Cardiovascular Medicine
• Molecular Biology
• Pharmacology

Background:

• Elevated low-density lipoprotein cholesterol (LDL-C) is a primary driver of cardiovascular heart disease (CHD).
• Statins, a common treatment, can cause severe side effects, necessitating alternative therapies for statin-intolerant patients.
• Monoclonal antibodies (mAbs) targeting PCSK9 effectively reduce LDL-C but require frequent injections and incur high costs.

Purpose of the Study:

• To engineer and characterize a DNA-encoded mAb (DMAb) targeting PCSK9 (daPCSK9) as a novel therapeutic approach.
• To evaluate the in vivo expression, activity, and cholesterol-lowering effects of daPCSK9.

Main Methods:

• Engineering of a DNA-encoded mAb (DMAb) targeting PCSK9.
• Single and repeated intramuscular administration of daPCSK9 plasmid in wild-type mice.
• Monitoring of in vivo DMAb expression and quantification of lipid levels (non-HDL-C, total cholesterol).

Main Results:

• A single intramuscular dose of daPCSK9 resulted in sustained in vivo expression for over 42 days.
• Significant reductions in lipid levels were observed: 28.6% decrease in non-high-density lipoprotein cholesterol (non-HDL-C) and 10.3% in total cholesterol by day 7.
• Repeated administrations led to increasing DMAb expression, reaching 7.5 μg/mL by day 62.

Conclusions:

• DNA-encoded mAbs targeting PCSK9 represent a promising alternative to protein-based therapeutics for LDL-C reduction.
• daPCSK9 offers a potentially simpler, less frequent, and more cost-effective treatment strategy.
• This approach may be valuable as a standalone therapy or in combination with other lipid-lowering agents for synergistic effects.