Emerging Pulmonary Delivery Strategies in Gene Therapy: State of the Art and Future Considerations
Anthony J. Hickey, Sandro R.P. da Rocha in Pharmaceutical Inhalation Aerosol Technology, 2019
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 Even if Glybera has been withdrawn in October 2017 due to lack of demand, its approval still represents the culmination of many years of research on DNA delivery with the help of viruses.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
John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie in Basic Sciences Endocrine Surgery Rhinology, 2018
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
Patricia G. Melloy in 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.
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.
Gene therapy trials for haemophilia: a step closer to a cure?
Published in Expert Review of Precision Medicine and Drug Development, 2019
Paul Batty, K John Pasi
We all recognize that gene therapy will potentially very expensive – Glybera (Alipogene tiparvovec), which was the first approved gene therapy agent for the treatment of lipoprotein lipase deficiency was marketed at $1 million (USD). Despite the significant financial burden that current approaches have in haemophilia, there will be a need to demonstrate cost-effectiveness for gene therapy. Recent data has been presented using a Markov state transition model to estimate costs and effectiveness (Quality-adjusted life years; QALYs) of gene therapy in comparison to prophylaxis using Medicare data [29]. Assuming gene therapy costs of $1 million, this strategy was superior over a 10 year time frame both in terms of cost ($1 million v $1.7 million) and QALYs (8.33 v 6.62) to standard prophylaxis. Nonetheless, cost will feature significantly in the equation about viability and use. Innovative models of payment will undoubtedly need to be developed. This could severely restrict access to treatment.
Nanotechnology-enabled gene delivery for cancer and other genetic diseases
Published in Expert Opinion on Drug Delivery, 2023
Tong Jiang, Karina Marie Gonzalez, Leyla Estrella Cordova, Jianqin Lu
Theoretically, due to the high specificity of pathogenic targets, gene therapy can regulate any genes related to pathogenesis, which is a blue moon with any other type of drug. Gene therapy agents can be exploited for gene correction, silencing, or suppression of the expression genes in any disease-related disease with a designed rational sequence. Second, high efficiency can be achieved by genetic agents such as researchers found that RNAi acts as an enzyme-mediated process [2], where a large number of mRNA targets could be cleaved by a single siRNA only. Another practical problem is that therapeutic reagents could tempt cytotoxicity readily while in a high-dose administration, therefore gene agents used in disease therapy should observe a standard of relatively infrequent, low to medium doses, which make it possible to reduce the side effects associated with clinical chemical drugs. Third, the final advantages of nucleic acid drug nominees are that they are rapid and easiest to develop. Bioinformatic tools can be used to customize gene sequences in accordance with disease targets [3] where this kind of straightforward candidate screening process makes nucleic acid drugs easy to design and develop. They are specifically appropriate for the therapy of rare diseases, which is hindered by lack of market and need to absorb support and resources to discover these necessary treatments. A variety of genetic drugs have been demonstrated and approved worldwide at present, including alipogene tiparvovec (Glybera) approved by the European Medicines Agency (EMA) aimed to lipoprotein enzyme deficiency therapy. FDA approved antiviral agents: fomivirsen (Vitravene) and pegaptanib (Macugen) were aimed for the treatment of senile macular degeneration (SMD).
Related Knowledge Centers
- Founder Effect
- Gene Therapy
- Immunosuppression
- Lipoprotein Lipase
- Retrovirus
- Cancer
- Pancreatitis
- Lipoprotein Lipase Deficiency
- Marketing Authorisation
- Adeno-Associated Virus