Related Experiment Video
Updated: May 30, 2025
08:54
Functional Human Liver Preservation and Recovery by Means of Subnormothermic Machine Perfusion
Published on: April 27, 2015
16.9K
AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion
Jae-Jun Kim1,2, Simone N T Kurial1,2,3, Pervinder K Choksi1,2,4
1Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
Nature Biotechnology
|January 29, 2025
Summary
Adeno-associated virus (AAV) liver gene therapy success hinges on capsid selection. AAV-LK03 shows superior efficiency and specificity in human liver models compared to common clinical AAVs, guiding future gene therapy development.
Area of Science:
- Gene Therapy
- Hepatology
- Virology
Background:
- Adeno-associated virus (AAV) capsid choice is critical for the efficacy and safety of liver gene therapy.
- Predicting AAV capsid performance in clinical settings is essential for successful therapeutic development.
Purpose of the Study:
- To compare the performance of different AAV capsids in human liver tissue under near-clinical conditions.
- To evaluate AAV capsid efficiency, specificity, and impact on vector episome formation in the context of steatosis and hepatocyte zonation.
Main Methods:
- Side-by-side comparison of AAV capsid performance using single-cell resolution in human livers.
- Utilizing normothermic machine perfusion to maintain human livers for ex vivo studies.
- Assessing transduction efficiency, cell tropism, and episome formation influenced by AAV capsid and liver steatosis.
Main Results:
- AAV-LK03 demonstrated significantly higher hepatocyte transduction efficiency and specificity compared to clinically used AAV5, AAV6, and AAV8, and AAV-NP59.
- AAV-LK03 targeted periportal hepatocytes in normal liver, while AAV5 targeted pericentral hepatocytes in steatotic liver.
- AAV5 and AAV8 exhibited high transduction rates in both hepatocytes and liver sinusoidal endothelial cells; AAV5 delayed vector concatemerization.
Conclusions:
- Findings guide the selection of AAV capsids for clinical liver gene therapy, considering hepatocyte zonation and steatosis.
- AAV-LK03 represents a promising candidate for efficient and specific hepatocyte transduction.
- This study facilitates the development of novel AAV capsids for targeted gene delivery in the human liver.
