AAV gene therapy for homozygous familial hypercholesterolemia: a phase 1 trial

Area of Science:

• Cardiovascular Medicine
• Gene Therapy
• Metabolic Disorders

Background:

• Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder causing extremely high LDL-C levels and premature cardiovascular disease.
• Most HoFH cases are linked to mutations in the low-density lipoprotein receptor (LDLR) gene, impairing LDL-C clearance.
• Current treatments often fall short for HoFH patients, highlighting the need for innovative therapeutic strategies.

Purpose of the Study:

• To develop and evaluate the safety and efficacy of an adeno-associated virus (AAV) gene therapy (NGGT006) for treating HoFH.
• To assess NGGT006's ability to restore LDLR expression and reduce LDL-C levels in preclinical models and human patients.

Main Methods:

• Developed NGGT006, an AAV serotype 8 vector encoding a codon-optimized LDLR complementary DNA.
• Tested NGGT006 in LDLR-deficient mice and hamsters to assess LDL-C reduction and plaque size.
• Administered NGGT006 to non-human primates to evaluate safety and tolerability.
• Conducted an open-label, single-arm, dose-escalation trial in three HoFH patients, monitoring safety and LDL-C levels over 52 weeks.

Main Results:

• NGGT006 successfully lowered LDL-C levels and reduced aortic plaque in animal models.
• In rhesus monkeys, NGGT006 caused transient liver enzyme elevations but no severe adverse events.
• HoFH patients tolerated NGGT006 well, with transient, manageable liver enzyme elevations.
• The highest dose group showed a significant and sustained reduction in LDL-C, from 11 mmol/L to below 1.8 mmol/L within 3 weeks.

Conclusions:

• NGGT006 gene therapy demonstrates promising safety and efficacy in lowering LDL-C in HoFH patients.
• The study provides initial evidence supporting the therapeutic potential of AAV-mediated LDLR gene therapy for HoFH.
• Further research is warranted to confirm the long-term safety and efficacy of NGGT006.