Low cholesterol syndrome and drug development.

Area of Science:

• Lipid metabolism
• Pharmacology
• Genetics

Background:

• Low cholesterol syndromes were historically overlooked.
• Recent research has illuminated the genetic basis and clinical implications of hypolipidaemic disorders.

Purpose of the Study:

• To review hypolipidaemic disorders.
• To discuss drugs developed from insights gained from these rare conditions.

Main Methods:

• Review of literature on genetic mutations causing low cholesterol.
• Analysis of drug development pathways informed by these genetic insights.

Main Results:

• Mutations in apolipoprotein B (apoB) or microsomal transfer protein cause abetalipopoproteinaemia and hypobetalipoproteinaemia, leading to mipomersen and lomitapide for homozygous familial hypercholesterolaemia.
• Loss-of-function PCSK9 mutations spurred the development of widely used PCSK9 antibody therapies for hypercholesterolaemia.
• Mutations in apolipoprotein C-3 (apoC-3) and angiopoietin-like protein 3 (ANGPTL3) cause hypolipoproteinaemia and reduced triglycerides, with antisense therapies and antibodies in development for familial chylomicronaemia syndrome.
• Activating mutations in apoA-1 suggest modifying high-density lipoprotein (HDL) turnover may reduce cardiovascular disease (CVD) risk.

Conclusions:

• Orphan lipid disorders offer crucial insights into cholesterol regulation mechanisms.
• These insights have driven the development of drugs for rare lipid diseases and general CVD risk reduction.