Single-dose AAV gene therapy for homozygous familial hypercholesterolemia (HoFH) achieves sustained LDL-C reduction from 11 mmol/L to below 1.8 mmol/L in Phase I trial, published in Nature Medicine.
• June 4, 2026 — Results published in Nature Medicine
• Single-dose AAV gene therapy — NGGT006 delivers functional LDLR gene to the liver
• Highest dose patient — LDL-C reduced from 11 mmol/L to <1.8 mmol/L
• Favorable safety — no vector-related serious adverse events
• First HoFH gene therapy trial conducted in China
Introduction
Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal dominant disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels and accelerated atherosclerotic cardiovascular disease.[reference:54] The prevalence is estimated at approximately 1 in 300,000.[reference:55]
Over 80% of HoFH patients carry mutations in the low-density lipoprotein receptor (LDLR) gene.[reference:56] The liver plays a central role in cholesterol homeostasis through LDLR-mediated clearance of LDL from the blood.[reference:57]
On June 4, 2026, a team from Xi'an Jiaotong University First Affiliated Hospital (Professors Wu Yue, Yuan Zuyi, Luo Yongbai, She Jianqing, and Chen Tao) published the Phase I trial results of NGGT006, an AAV-based gene therapy for HoFH, in Nature Medicine.[reference:58][reference:59]
The NGGT006 Gene Therapy
NGGT006 is a recombinant AAV serotype 8 (AAV8)-based gene therapy vector containing a codon-optimized LDLR complementary DNA.[reference:60] The vector is designed to deliver a functional LDLR gene to hepatocytes, restoring the liver's ability to clear LDL from the blood.[reference:61]
Key features of the AAV8 vector:
- Liver tropism — AAV8 has high natural affinity for hepatocytes
- Single-dose administration — designed for one-time treatment[reference:62]
- Long-term expression — AAV vectors can provide sustained transgene expression
Preclinical Studies
Preclinical studies demonstrated:[reference:63]
- NGGT006 reduced LDL-C levels in Ldlr−/− mice and hamsters
- Aortic plaque area was reduced in Ldlr−/− mice
- In rhesus macaques, transient liver enzyme elevations were observed but no serious adverse events occurred
Phase I Clinical Trial
The Phase I trial was an open-label, single-arm, dose-escalation study enrolling three HoFH patients who received NGGT006 at doses of 7.5×10¹², 1.5×10¹³, and 3×10¹³ vg/kg, respectively.[reference:64]
Study Design
| Parameter | Details |
|---|---|
| Lead Institution | Xi'an Jiaotong University First Affiliated Hospital |
| Drug Candidate | NGGT006 (AAV8-LDLR) |
| Number of Patients | 3 HoFH patients |
| Dose Escalation | 7.5×10¹², 1.5×10¹³, 3×10¹³ vg/kg |
| Primary Endpoint | Safety and LDL-C reduction at 52 weeks |
Safety Results
NGGT006 was well-tolerated with no vector-related serious adverse events:[reference:65]
- Liver enzyme elevations — observed in all three patients but normalized with sirolimus and methylprednisolone treatment[reference:66]
- No serious adverse events related to the vector were reported[reference:67]
- Transient immune responses were manageable with standard immunosuppression
Efficacy Results
The efficacy data were striking:[reference:68]
- Highest-dose patient — LDL-C decreased from 11 mmol/L at baseline to below 1.8 mmol/L starting at week 3
- Sustained reduction — the effect was maintained through the 52-week follow-up period
- Guideline targets achieved — the patient reached the recommended LDL-C goal for high-risk patients
As the investigators noted: "These results provide preliminary evidence of the safety and therapeutic potential of NGGT006, laying the foundation for further safety and efficacy studies."[reference:69]
Significance for HoFH Patients
This breakthrough has profound implications for HoFH patients:[reference:70]
- Current therapies are inadequate — statins, ezetimibe, and PCSK9 inhibitors all depend on LDLR activity and often fail to achieve guideline-recommended LDL-C targets in HoFH patients
- ANGPTL3 inhibitors offer a non-LDLR-dependent pathway but require lifelong administration and have uncertain long-term safety[reference:71]
- Gene therapy offers a one-time treatment — potentially eliminating the need for lifelong lipid-lowering therapy[reference:72]
- Fills a global gap — this is the first gene therapy trial for HoFH conducted in China[reference:73]
Future Directions
The research team plans to:[reference:74]
- Expand the trial to include more patients
- Conduct longer-term follow-up to assess durability of the response
- Explore optimization of the immunosuppression regimen
- Evaluate the therapy in broader HoFH populations
This study represents a major step forward in the treatment of HoFH, demonstrating that single-dose AAV gene therapy can achieve meaningful and sustained LDL-C reduction in patients with this devastating disease.[reference:75]