## 4 The Application of rAAV Produced by BEVS in Gene Therapy  
As an important vector of gene therapy, the recombinant AAV has been widely used in the treatment of many genetic diseases because of its excellent safety and long-term gene expression ability. At present, eight gene therapy drugs based on rAAV have been approved for marketing in the United States and Europe (Table 3). \begin{table}
\begin{tabular}{c c c c c c c c} \hline
**Time to Market** & **Drug Name** & **Carrying Gene** & **R\&D Company** & **Indications** & **Injection Method** & **Production System** & **References** \\ \hline
2012 & Glybers (aliposome & AAV1-1 PL & uniQuere (Almerce, The Netherlands) & lipoprotein lipase & intramuscular injection & Bac/SP/ systems & [88] \\  & tptavovev) & The Netherlands & deficiency (JFLD) & & & & \\
2017 & Luxtman (voretiegine & AAV2-RFE65 & Spark/Roche (Haseel, & RPE55 mutation-related & & subretinal injection & HEK293 systems & [89] \\  & naparovec-vzyl) & AAV2-RFE65 & Switzerland) & hereditary retinopathy & & & \\
2019 & Zolgerman (onasemogene & AAV9-SMN1 & Axels/Novarts & Spinal muscular atrophy & & \\  & aberarovec) & AAV9-SMN1 & (Basel, Switzerland) & (SMA) & intramuscular injection & HEK93 systems & [90] \\  & Upstaza (eladocagine & AAV2-AADC & PTC Therapeutics & Aromatic Landin acid & & \\  & exparovec) & & (Warner, NJ, USA) & decarboxylase (AADC) & intracerebral injection & HEK293 systems & [91] \\  & Rectavin (valectogen & AUV5-hFVIII & BioMarin San Rafed, CA, USA) & Hemophilia A & intramuscular injection & Bac/SP/ systems & [92] \\  & roasparovec) & AAV5-hFVII & (SCN,/uuQuere & & & & \\  & Hemgenix (etranacogene & & (Amsterdam, The Netherlands) & Hemophilia B & intramuscular injection & Bac/SP/ systems & [93] \\  & dezaquervove-drll) & & Netherlands) & & & & \\  & Elevidys (delandstone & AAV2-micro- & Serenfa/Roche & Daschene muscular & & \\  & macquervove-cold) & dystrophin & (Cambridge, MA, USA) & dystrophy (DMD) & intramuscular injection & HEK93 systems & [94] \\  & Bequez/ Durvegitix & & & & & & \\
2024 & (fidanacogene & alparvove) & AWith7-war-hFIX & Prize (New York, NY, USA) & Hemophilia B & intramuscular injection & HEK93 systems & [93] \\ \hline \end{tabular}
\end{table} 
Table 3: Gene therapy drugs based on rAAV. Among them, three species were produced by the Sf9 insect cell system. The first rAAV gene therapy drug on the market, Glybera from the uniQure Company, uses the IC-BEVS to produce rAAV, which delivers the gene producing functional lipoprotein lipase to the skeletal muscle of patients to treat lipoprotein lipase deficiency. Although it was delisted in 2017, the listing of this first gene therapy drug made a milestone breakthrough for BEVS in the field of AAV gene therapy [88; 96]. In August 2022, BioMarin made the gene therapy drug Roctavian (Valococogene roxapavovec) for X-linked hemorrhagic disease (hemophilia A) caused by F VIII gene defects. By using the AAV5 vector to deliver F VIII, the patient's need for factor replacement therapy is significantly reduced [92; 97]. In November 2022, uniQure developed the gene therapy drug Hemgenix (Ettanacogene dezapavovec) for X-linked hemorrhagic disease (hemophilia B) caused by F IX gene defects. Clinical trial data showed that patients treated with intravenous injection of AAV5-hFIX had a significant increase in the level of F IX, reduced the occurrence of bleeding events, and had good safety [93]. Moreover, rAAV produced by the insect Sf9/Bac system also accounts for a considerable proportion of AAV gene therapy that has been approved for clinical trials at home and abroad [28]. In October 2022, [PERSON] and others conducted a meta-analysis of 255 clinical trials to evaluate the immunogenicity, toxicity and characteristics of AAV gene therapy in the clinical environment. Among the 186 trials in which the information of production system has been disclosed, 63.0% (\(n=126\)) used the transient transfection HEK293/HEK293T system, and 18.0% (\(n=36\)) used the baculovirus /Sf9 system.