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36 Pharmaceutical Technology ® Trends in Formulation 2022 eBook PharmTech.com SVETA - STOCK.ADOBE.COM A lthough gene therapy was initially con- ceptualized as early as the 1960s (1), the first successful gene therapy in humans was in the 90s in which a gene-mod- ified cell therapy for the treatment of adenosine deaminase (ADA)-deficient severe combined im- munodeficiency (2). T-cells were collected through apheresis and transformed using a retrovirus carry- ing a functional ADAs gene before reinfusion. Since then, the industry has continuously evolved. Gene therapy has rapidly expanded conceptually and tech- nically, now covering a wide array of tools and meth- ods, including the advancement of viral vector deliv- ery for gene therapies. Lentiviral vectors and adeno-associated virus (AAV) are two primary delivery mechanisms of gene thera- pies. Originally identified as a contaminant in adeno- virus virus cultures, AAV was later revealed to have the ability to integrate into the host genome, and thus the potential of AAV as a therapy vector was discov- ered (3). AAVs are versatile vectors, due in large part to their large variant numbers (more than 5000), ex- tensive tropism profiles, and low immunogenicity (4,5). Lentiviruses are conversely much larger than AAV at 9.7 kb. Therapeutic lentiviruses are predomi- nately derived from human immunodeficiency virus 1 (HIV-1) but have been engineered to be non-replicat- ing. Like AAV, lentiviruses are retroviruses capable of integrating their genetic cargo, but not the virus-cod- ing sequence, into the host genome (6,7). Unlike other retroviruses, which require active cell division, len- tiviruses can also infect and integrate into typically Addressing Developmental Challenges of Gene Therapy Viral Vectors Ger Brophy, is the executive vice-president of Biopharma Production, Arvind Srivastava is a technical fellow, Bioprocessing, and Greg Swan is business development manager for Cell & Gene Therapy; all are at Avantor. Significant improvements have been developed to tackle the challenges in viral vector manufacturing at each stage.