Ethan He Gene Therapy

Adeno-associated virus gene therapy

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The gene therapy model using adeno-associated virus (AAV) has gradually entered the stage of commercial development. Analysis of 149 studies of AAV gene therapy showed that 59 of them reached the clinical end point. The modification of AAV capsids (AAV2, AAV8, AAV9, AAV-LK03, SPK-100 and AAV-HSC15) has also been studied in different disease models. However, the specific expression of strong promoter in tissues and the toxicity caused by the immune response of capsid are still important obstacles.


At present, it is mainly concentrated in five organs: eye, liver, muscle, central nervous system and blood system. 36% of the drugs progressed from IND to NDA, and the median development time was 86 months. The success rate of blood system was the highest (56% of patients could enter NDA stage from IND). 31% in Ophthalmology, 30% in nervous system and 23% in muscular system. AAV treatment for heart, kidney and lung is still not available (1). A 3-year follow-up study of AAV5-hFVⅢ-SQ in the treatment of hemophilia A reported the long-term safety and efficacy of 15 patients with severe hemophilia A. In this study, the level of factor Ⅷ, the annual incidence of bleeding events, safety, biomarkers and expression kinetics were evaluated. The results showed that AAV5-hFVⅢ-SQ treatment could bring sustained clinical benefits in patients with severe hemophilia A, the annualized rate of bleeding events decreased significantly, and the use of prophylactic factor Ⅷ was basically stopped (2). Although no serious liver injury events (such as significant elevation of transaminase and other indicators of liver injury) were reported in this study, the toxic effects on liver need to continue to be monitored with the continuous expression of vector. This study fully confirmed the feasibility of AAV in the treatment of hematological diseases.


As a tool and system for gene delivery and expression, AAV gene therapy can replace, silence, add and edit mutant genes by single base. However, the unacceptable high price of production cost makes patients unable to afford it. For example, the price of Glybera approved by EMA for lipoprteinlipase deficiency in 2021 is up to 1.2 million dollars. Luxturna, approved in 2017, is used to treat genetic retinopathy with a mutation in the RPE65 gene, which also costs as much as $400,000 per eye. The production process of AAV is quite different from traditional drug production, which is high standard and difficult to standardize. AAV may induce neutralization antibody production through toll like receptor pathway (such as TLR2), which will affect the clinical effect of AAV treatment, and its mechanism needs to be further clarified. The toxic effect of AAV therapy may also affect its clinical application. The central nervous system of primates is related to the neurodegeneration of dorsal root ganglion (DRG). This may be related to the high level of AAV transduction in DRG cell damage. The endogenous expression of mir183 complex in DRG neurons can specifically reduce the toxicity of DRG (4). The association between AAV and liver cancer has also raised concerns about its genotoxicity. However, a large-scale molecular epidemiological study from China seems to reduce our concerns. This survey showed that AAV2/3 serotype is the most common serotype in tumor tissues, and AAV genome is also abundant in tumor and adjacent normal tissues, but lack of clonality, thus, there is no causal relationship with the occurrence of tumor (5). In the design process of AAV capsid, we can use deep learning to design a highly diverse variant Library of AAV capsid protein. For 28 amino acid segments, machine learning can generate 201,426 variant libraries of AAV2 wild-type sequences. At the same time, according to the deep neural network model, we can accurately predict 110,689 feasible engineering capsids (6). This may greatly optimize the design of AAV and shorten the development cycle, combined with the screening of cell and animal models, and improve the efficacy and safety of AAV gene therapy drugs.



1, Kuzmin DA, et al. Nat Rev Drug Discov. 2021;20:173-174.

2, Pasi KJ, et al. N Engl J Med. 2020;382:29-40.

3, Wang D, et al. Nat Rev Drug Discov. 2019;18:358-378.

4, Hordeaux J, et al. Sci Transl Med. 2020;12:eaba9188.

5, Qin WR, et al. Oncogene. 2021;40:3060-3071.

6, Bryant DH, et al. Nat Biotechnol. 2021 Feb 11.

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