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Emerging Pulmonary Delivery Strategies in Gene Therapy: State of the Art and Future Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Gabriella Costabile, Olivia M. Merkel
In 2012, the European Medicines Agency (EMA) approved Glybera (alipogene tiparvovec) as the first gene therapy treatment for sale in the European Union. Even if Glybera has been withdrawn in October 2017 due to lack of demand, its approval still represents the culmination of many years of research on DNA delivery with the help of viruses. In fact, Glybera is an adeno-associated virus (AAV)-mediated delivery of DNA for the treatment of the inherited metabolic disorder lipoprotein lipase deficiency (Yla-Herttuala 2012, Schuster, 2013, 2014, Ferreira et al. 2014, Watanabe et al. 2015, Mullard 2016).
Gene Therapy
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Seiji B. Shibata, Scott M. Graham
Gene therapy is the means of delivering exogenous genetic material for therapeutic purposes into the host cell target using vectors. This strategy in principle can be utilized in patients who have genetic defects leading to phenotypic impairment. Gene therapy can be restorative, regenerative or protective in nature by replacing/suppressing/enhancing gene expression. Few new treatment protocols reflect the allure of modern science quite as elegantly as gene therapy. The promise of gene therapy in treating a variety of diseases is, simply put, incredible. This promise has captured the hopes and enthusiasm of the scientific and lay communities alike. Notable initial success in treating severe combined immune deficiency (SCID) seemed to herald imminent success in treating a whole variety of other conditions. In reality, however, progress in bringing the allure of the science to a useful clinical application has been quite limited. Even in the group of SCID subjects1 – an apparent ‘cure’ – a patient has died from an unusual lymphoproliferative disease.2 This has led to a reassessment of the risks of retroviral therapy trials. While great strides have been made in understanding the microbiological complexities of disease states and vectors, the barriers to clinical utility continue to be formidable. However in recent years gene therapy has met major milestones in multiple clinical trials for a number of diseases including Leber’s congenital amaurosis,3, 4 X-linked adrenoleukodystrophy5 and β-thalassemia.6 In the 10-year follow-up study of aforementioned SCID subjects, 18 out of 20 patients are still alive, including four who had leukemia and 17 who have their immunodifficiency corrected.7 Additionally the European commission has recently approved alipogene tiparvovec (Glybera®), an AAV viral vector harbouring human lipoprotein lipase, which will be used for the treatment of familial lipoprotein lipase deficiency disease, making it the first commercial available drug using gene therapy technology in Europe.8 Thus, after experiencing several major setbacks gene therapy is making small but steady steps towards clinical reality.
Recombinant DNA Technology and Gene Therapy Using Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
Starting 30 years ago, researchers explored the use of gene therapy to treat severe combined immunodeficiency (SCID), a disorder in which the patient’s immune system never fully develops making the person prone to acquiring life-threatening infections. Researchers focused on two forms of SCID, caused by different genes. For adenine deaminase–severe combined immunodeficiency (ADA-SCID), a retroviral vector was used to replace the defective ADA gene, using an ex vivo approach where the patient’s T cells were modified and then transplanted back into the body. It is believed that the therapy worked, but patients were receiving an enzyme-based treatment during the entire gene therapy course. Another form of SCID involving a mutation in a gene on the X chromosome (X-SCID) was also treated using a retroviral vector. However, several children in the trial developed leukemia a few years after treatment, most likely due to a viral integration event affecting cell growth regulation (Minkoff and Baker 2004; Lostroh 2019; Colavito 2007; Kurreck and Stein 2016; Anguela and High 2019; Dunbar et al. 2018). An adverse outcome was also seen with a gene therapy trial to treat a deficiency in the metabolic enzyme ornithine transcarbamylase in 1999. One patient died and the trial was halted (Lostroh 2019; Colavito 2007; Mukherjee 2016; Minkoff and Baker 2004). This tragedy prompted a period of basic research into new viral vector delivery systems and more oversight of gene therapy trials that continues to this day (Collins and Gottlieb 2019). Since that time, new technologies have been used to tackle SCID. Strimvelis is a type of gene therapy product using an updated viral vector delivery system to treat ADA-SCID patients. However, demand for this new therapy is quite low due to the small number of patients with the disease, and it is unclear how long the product will be marketed (Anguela and High 2019; Li and Samulski 2020; Aiuti, Roncarolo, and Naldini 2017; Dunbar et al. 2018). Another gene therapy product, alipogene tiparvovec, also known as Glybera, is used to treat familial lipoprotein lipase deficiency using an AAV vector. It was approved for use in Europe in 2012 (Lostroh 2019; Kurreck and Stein 2016; Wang, Tai, and Gao 2019; Li and Samulski 2020). However, the treatment is quite expensive, costing over a million dollars a treatment (Kurreck and Stein 2016). Glybera is no longer being marketed in Europe (Shahryari et al. 2019). Rexin-G is an anti-cancer gene therapy that works by blocking cell cycle progression by expressing a modified version of a gene called cyclin G using a retroviral vector. It is being tested right now in clinical trials of people with advanced pancreatic cancer (Lostroh 2019; Shahryari et al. 2019). Although the development of gene therapy treatments is a long road with many possible setbacks, several gene therapy products are approved for use in the United States right now, as described next.
Gene therapy for inherited retinal diseases: progress and possibilities
Published in Clinical and Experimental Optometry, 2021
Monica L Hu, Thomas L Edwards, Fleur O’Hare, Doron G Hickey, Jiang-Hui Wang, Zhengyang Liu, Lauren N Ayton
Gene therapy has been explored for a myriad of therapeutic applications. In 1990, the first gene therapy trial commenced in two children with adenosine deaminase deficiency leading to severe combined immunodeficiency, and used white blood cells modified ex vivo to express the deficient adenosine deaminase gene.13 Later, safety issues were indelibly highlighted in 1999 when a fatal immune reaction to an adenovirus vector resulted in the first death of a gene therapy trial patient. Further investigations proceeded with caution and by 2003, China was the first to approve an ex vivo gene therapy product for commercial use—Gendicine (SiBiono GeneTech, China), an adenovirus vector to treat head and neck squamous cell carcinoma.13 Thereafter, the European Union in 2012 approved alipogene tiparvovec (Glybera, uniQure, Netherlands), a recombinant adeno-associated virus for the treatment of familial lipoprotein lipase deficiency.14 In 2017, the US Food and Drug Administration (FDA) approved its first gene therapies: tisagenlecleucel (Kymriah, Novartis, USA), a chimeric antigen receptor T-cell immunotherapy for acute lymphoblastic leukaemia,15 and later voretigene neparvovec (Luxturna, Spark Therapeutics, USA), an adeno-associated virus vector carrying the RPE65 gene for RPE65-associated Leber congenital amaurosis. Luxturna represents a major milestone in ocular gene therapy advancement and was also recently registered by the Australian Therapeutic Goods Association in August 2020, becoming the first approved in vivo gene therapy in Australia.
Ocular gene therapy for choroideremia: clinical trials and future perspectives
Published in Expert Review of Ophthalmology, 2018
Kanmin Xue, Robert E. MacLaren
The first ever AAV-based gene therapy, alipogene tiparvovec (Glybera, Uniqure, the Netherlands), was approved by the European Medicines Agency (EMA) in 2012 for the treatment of familial lipoprotein lipase deficiency (LPLD). More recently, the Food and Drug Administration (FDA) has approved voretigene neparvovec-rzyl (LUXTURNA®, Spark Therapeutics Inc., USA) to treat Lebers congenital amaurosis (LCA) due to mutations in RPE65 [64]. The latter represents the first retinal gene therapy to receive FDA approval and provides great impetus for similar AAV-based gene replacement approaches to treat other inherited retinal diseases. Interestingly, given the profound nature of visual impairment in RPE65 LCA, the primary outcome measure employed was a validated visual navigation test rather than visual acuity. This represents a welcome recognition that simplistic standard functional visual tests such as BCVA may not be adequate to demonstrate the full benefits of novel therapies in RP patients with complex visual impairment.
Advances in diagnosis and potential therapeutic options for familial chylomicronemia syndrome
Published in Expert Opinion on Orphan Drugs, 2018
Lane B. Benes, Eric J. Brandt, Michael H. Davidson
For those with FCS due to LPL deficiency, enzyme replacement with LPL infusion is not feasible due to very short half-life. Alipogene tiparvovec (Glybera, UniQure, Amsterdam, The Netherlands) encodes a naturally occurring gain-of-function LPL variant that is transcribed after intramuscular injection. One of the initial trials gave 14 patients with FCS due to LPL deficiency alipogene tiparvovec in addition to a low-fat diet, 12 of which were also given immunosuppression with cyclosporine A or mycophenolate mofetil to prevent immune response to the capsid proteins involved in gene delivery [65]. Two of the 14 participants had no TG reduction and the other 12 had an average reduction of 39.5% from baseline 3–12 weeks after administration, 4 of which achieved TG < 10 mmol/L (880 mg/dL). Serum TG returned to baseline about 5 months after treatment. Two years after treatment, the variant gain-of-function LPL was still detected on muscle biopsy [65]. All participants demonstrated an immune response with anti-capsid antibodies, which did not appear to be affected by giving prophylactic immune suppression. In the 2-year follow-up period, the risk of acute pancreatitis dropped fivefold despite having a return to baseline TG after 16–26 weeks [65]. This was postulated to be due to change in chylomicron and other TRL composition and kinetics [65]. There were no serious adverse effects acutely or through 2 years of follow-up [65]. A later analysis by Gaudet et al. published in 2016 reviewed medical record information for 19 patients with LPL deficiency up to 6 years after receiving alipogene tiparvovec, finding a large reduction in episodes of acute pancreatitis and abdominal pain, as well as a large reduction in hospitalizations [66].