Genetic therapies to lower cholesterol

Area of Science:

• Genetics
• Cardiovascular Medicine
• Molecular Biology

Background:

• Familial hypercholesterolaemia (FH) is a genetic disorder causing severely high LDL cholesterol and premature atherosclerosis.
• Current FH pharmacological treatments are often inadequate, costly, and associated with adverse effects.
• Previous gene replacement therapies for FH have faced challenges.

Purpose of the Study:

• To review the current landscape of genetic therapies for FH.
• To introduce a novel therapeutic concept, APO-skip, for FH treatment.
• To highlight the potential of APO-skip as a safe, effective, and cost-efficient FH therapy.

Main Methods:

• Review of existing literature on FH genetic therapies.
• Exploration of Apolipoprotein B100 (APOB100) and PCSK9 inhibition strategies.
• Introduction of the APO-skip concept targeting APOB splicing modulation.

Main Results:

• Gene replacement strategies using viral vectors have shown limited success.
• APOB100 knockdown therapies like mipomersen have efficacy but also adverse effects.
• The APO-skip concept presents a new approach to FH treatment.

Conclusions:

• There is a need for improved FH therapies beyond current pharmacological options.
• APO-skip offers a promising novel strategy for FH management.
• This approach has the potential for a cost-effective, efficacious, and safe FH therapy.