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Gene therapy of haemophilia continues to tantalize patients and clinicians alike. Phase III of three different clinical trials (one for haemophilia A and two for haemophilia B) will soon commence.1-3 Recently published phase II results showed the curative potential of these gene therapies, with seven patients (six with haemophilia A and one with haemophilia B) achieving normal levels of coagulation factor VIII or IX (FVIII:C and FIX:C), which persisted over up to 52 weeks after gene transfer.1, 2 Therefore, it seems that gene therapy for haemophilia is well on its way to ultimately transform the lives of patients, who still mostly rely on frequent intravenous infusions of coagulation factor concentrates to prevent and treat bleeds. It has been a long and winding road for haemophilia gene therapies to arrive at the current state of the art. Early promising results in animal haemophilia models in the mid-1990s proved difficult to replicate in human trials.4-7 In addition, while haemophilia studies were progressing, the gene therapy field as a whole was hit by major failures, the most tragic of which was the death of Jesse Gelsinger, who participated in a trial of gene therapy for ornithine transcarbamylase deficiency.8 The spectre of disaster particularly beset heamophilia investigators because the history of haemophilia care was already marred by the HCV and HIV epidemics caused by contaminated plasma-derived coagulation factor concentrates in the 1980s.9, 10 With such grim legacy, nobody could afford brinkmanship in the development of new haemophilia therapies. Since publication of the seminal paper by Herzog and co-workers,5 adeno-associated viral (AAV) vectors became the lodestar for gene therapy champions and indeed all the three leading clinical studies, as well as eight less advanced, rely on AAV vectors manufactured in mammalian (HEK293) or insect (Sf9 and its daughter subclone Sf900+) cell lines.11 In the April issue of Protein Expression and Purification, Geisler and Jarvis report that most insect cell lines used in research and manufacture of biologicals are persistently infected with adventitious viruses.12 Cell lines derived from ovarian cells of the fall armyworm (Spodoptera frugiperda), including Sf9, have been the workhorse for production of recombinant proteins in the baculovirus expression vector system (BEVS) since 1980s.13 This system has now become an established platform for the production of biologicals for research, veterinary and clinical use.14, 15 The list of licensed human therapeutics produced in BEVS includes vaccines against the human papillomavirus (this vaccine is manufactured in ovarian cells of the cabbage looper, Trichoplusia ni) and influenza as well as a prostate cancer immunotherapeutic and, most notably, gene therapy for lipoprotein lipase deficiency, the first ever licensed gene therapy (now withdrawn from the market for lack of interest).15, 16 Since 2002, Sf9 and BEVS have been adopted to manufacture AAV vectors.17 Geisler and Jarvis report that various Spodoptera frugiperda-derived cell lines, including Sf9 and Sf900+, are persistently infected with Sf-rhabdovirus.12 Most Spodoptera frugiperda-derived cell lines originated from a single progenitor cell line Sf-21, which turned out to be infected too and likely itself inherited the infection from the insect it was derived from. The virus is shed into the culture medium, which may contain 0.9-2.9 × 107 viral genomes/mL. The infection causes no obvious cytopathic effects, which is one of the reasons why it long went unnoticed. The virus does not infect mammalian cells and is considered to be nonpathogenic to humans. Nevertheless, the finding gives rise to questions about the safety of gene therapy and underscores the need for stringent safety measures. Notably, although Sf9 is refractory to many viruses found in other insect cell lines, it is susceptible to arboviruses. This is important insofar that many arboviruses can also infect vertebrates and cause serious disease in humans. Known arboviral human pathogens that can productively infect Sf9 cells include St. Louis encephalitis, Japanese B encephalitis, Dengue type 1 and 2, and Chikungunya viruses. Importantly, there are no reports of serendipitously detected persistent arboviral infections in Sf9 cells.12 In response to the universal Sf-rhabdovirus infection of Spodoptera frugiperda-derived cell lines, a new, rhabdovirus-free cell line named Sf-RVN has recently been generated. No other adventitious viruses have been detected in Sf-RVN, altogether making it a superior host for production of safe biologicals.18, 19 Although Sf-RVN cells are susceptible to Sf-rhabdovirus infection, they can be kept virus-free, even in facilities with a history of Sf-rhabdovirus-contaminated cell culture.12 Of interest to AAV vector manufacturers, the cell line may offer better AAV vector yields due to the lack of metabolic load imposed by a replicating adventitious virus. Limited yields continue to be a challenge in terms of scalability of the AAV vector production.20 So far, the frontline gene therapies for haemophilia in clinical trials proved to be effective and safe, and so the cure, so long coveted by the haemophilia community, came within reach. However, it is important that reports on gene therapy for haemophilia also describe the safety measures taken upstream from the patient level, including the steps to detect, remove, inactivate or prevent adventitious viral infections of cell lines employed to manufacture AAV vectors. Because of the past HIV and HCV fiascoes, and the unceasing attention to viral safety thereafter, this aspect of gene therapy is germane to the general discussion about its safety. The past disaster, together with the failure to properly inform the haemophilia community on the situation at the time, conditioned the patients for many years to feel that a danger was lying in wait. Although the potential safety risks related to adventitious viral infections of cell lines seem extremely small, it is important to openly and fully communicate them to the haemophilia community. The author stated that he had no interests which might be perceived as posing a conflict or bias.