LDLR-Gene therapy for familial hypercholesterolaemia: problems, progress, and perspectives.

Area of Science:

• Cardiovascular Medicine and Genetics
• Gene Therapy and Vectorology
• Metabolic Disorders

Background:

• Familial hypercholesterolemia (FH), a Mendelian disorder caused by low-density lipoprotein receptor (LDLR) deficiency, is a major risk factor for coronary artery disease (CAD).
• Current FH management focuses on controlling hypercholesterolemia to prevent atherosclerosis and CAD, with no definitive cure available.
• Gene therapy offers a potential permanent solution for FH, with the first clinical trial conducted 18 years ago.

Purpose of the Study:

• To review the progress in gene therapy for FH over the past 18 years since the first clinical trial.
• To evaluate the development, performance, and limitations of viral gene transfer vectors used in FH studies.
• To highlight advancements in vector design for ameliorating LDLR deficiency and lowering LDL-C serum levels.

Main Methods:

• Review of ex vivo gene therapy trials using retroviral vectors for LDLR-deficient hepatocytes.
• Analysis of in vivo preclinical studies employing adenovirus-mediated gene transfer.
• Examination of novel adeno-associated virus (AAV) and lentivirus vectors for long-term gene persistence.
• Inclusion of recently developed non-viral therapies for lowering LDL-C.

Main Results:

• The initial ex vivo retroviral gene therapy trial showed limited LDLR gene expression in FH patients.
• In vivo adenovirus gene transfer demonstrated effective hypercholesterolemia reversal but faced limitations in persistence and immunogenicity.
• Emerging AAV and lentivirus vectors show promise for long-term gene expression and safety in preclinical investigations.

Conclusions:

• Significant progress has been made in viral vector-based gene therapy for FH over 18 years.
• Current research focuses on developing safer and more persistent vectors, including AAV and lentiviruses, for clinical application.
• Novel non-viral therapies are also emerging as potential treatments for FH.