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Molecular Biology and Gene Therapy
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
Restoring the function of a key cellular gene whose dysfunction has resulted in cancer progression is a major goal of gene therapy. The most common mutations of key genes in squamous cell cancer of the head and neck are p53 and p16. p53 plays a role in triggering cell death in many different pathways involving apoptosis. Gendicine®, a drug with modified adenovirus harbouring p53 gene, was approved in China in 2004, becoming the first gene therapy approved for clinical use in humans. However, the western version of Ad-p53 (Advexin®) for the treatment of head and neck cancer was refused approval by the U. S. Food and Drug Administration in 2008.
Clinical Aspects of Head and Neck Cancer
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
Targeted therapy as well as gene therapy promises to improve the outcome of laryngeal cancer treatment in the near future. A significant association between the expression of p53 and poor patient outcome was found in patients with laryngeal carcinomas (Nylander 2000). Since in most laryngeal cancers the function of p53 gene is down regulated Wang et al. (1999) have explored the potential use of p53 in gene therapy of laryngeal cancer. The group has introduced a wild-type p53 into a laryngeal cancer cell line via a recombinant adenoviral vector and concluded that the adenovirus-mediated antitumour therapy is effective in inhibiting laryngeal cancer growth. After conducting a phase I clinical trial they have proven the effectiveness of recombinant adenovirus p53 injection (gendicine) in reducing laryngeal cancer progression (Han 2003). The 5-year relapse free survival was 100%. Further trials employing the adenoviral vector (Adp53) have shown that gendicine in combination with radiation show a synergistic effect in HNC (Zhang 2005).
Virus Wars
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Markus Vähä-Koskela, Fabrice Le Boeuf, Vincenzo Cerullo
So far, two oncolytic viruses have been approved for use in cancer treatment in China: Gendicine (Ad5-ΔE1B55K-p53) by Shenzhen SiBiono GeneTech in 2003 and Oncorine (H101, Ad5-ΔE1B55K-TK) by Sunway Biotech in 2005. In other parts of
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.
The current status of gene therapy in bladder cancer
Published in Expert Review of Anticancer Therapy, 2023
Côme Tholomier, Alberto Martini, Sharada Mokkapati, Colin P. Dinney
Despite initial reticence, the first gene therapy was approved in China in 2003, Gendicine, a recombinant human p53 adenovirus for head and neck cancer. A few years later, in 2012, the European Medicines Agency approved Glybera, an adeno-associated virus serotype 1 that delivers a normal copy of the human lipoprotein lipase gene to individuals affected by lipoprotein lipase deficiency. The FDA approved its first gene therapy in 2017, Kymriah, a CD-19 directed genetically modified T-cell for patients with follicular lymphoma. Since the initial approval nearly two decades ago, many gene-based therapeutic options are available in clinical practice across the world.
Next-generation viral nanoparticles for targeted delivery of therapeutics: Fundamentals, methods, biomedical applications, and challenges
Published in Expert Opinion on Drug Delivery, 2023
Jia Sen Tan, Muhamad Norizwan Bin Jaffar Ali, Bee Koon Gan, Wen Siang Tan
Gene therapy is an approach to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic purposes [88]. Approximately 59% of the 22 gene therapy products approved for human use are based on VNPs [89]. This platform is also being used by more than 70% gene therapy programs in clinical trials [89]. Among the VNPs, retrovirus, adenovirus (Ad), adeno-associated virus (AAV), and lentivirus are the major players as they act as viral vectors in gene delivery. Retroviral vector allows integration into a host DNA, which offers long-term gene expression in dividing cells [90]. Using this vector, a treatment for metastatic cancer has been developed; Rexin-GⓇ, which displays a specific collagen-binding motif that accumulates at cancerous lesions, and inhibits tumor growth by expressing cytocidal protein dnG1 [91,92]. Meanwhile, for Ad vectors, the gene carried is not integrated into a host genome, therefore it provides temporary gene expression in relatively broader host cells [78]. For example, GendicineⓇ was developed using a replication incompetent Ad5 carrying p53 gene. By injecting GendicineⓇ into tumors, the Ad can infect the tumor cells, and increase p53 protein expression leading to cell cycle arrest and apoptosis [93,94]. Unlike retrovirus, AAV does not integrate its gene into a host genome, and it has lower immunogenicity [95]. Therefore, it is one of the vectors of choice in gene delivery. AAV-based therapy, LuxturnaTM, has been successfully used to deliver the RPE65 gene to treat biallelic RPE65 mutation-associated retinal dystrophy [96,97], while ZolgensmaⓇ delivers SMN1 transgene required for effective function of the nervous system [98,99]. Meanwhile, lentivirus (LV) offers vast advantages as a viral vector as it can carry large foreign DNA fragments (up to 9 kb) into dividing and non-dividing cells, integrate them into the host genomes which promotes long-term expression [100]. Recently, a phase 2 clinical trial (NCT01852071, NCT02999984, and NCT01380990) on LV gene therapy to treat severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) demonstrated that the treatment resulted in overall survival of 100% up to 24 and 36 months. The drug, OTL-101, which is composed of ex vivo transduced hematopoietic stem and progenitor cells (HSPCs) with a self-inactivating lentiviral vector encoding human ADA, was shown to express ADA sustainably and persist in 96% of participants through the study duration [101]. Despite their strengths in gene delivery, each of these platforms have their own weaknesses; AAV has low packaging capacity (~4.5 kb) [100], retroviral vector cannot transduce non-dividing cells [102], Ad is highly immunogenic [90] while LV poses the risk of insertional mutations [100]. Therefore, in selecting a viral vector for gene therapy, strengths and weaknesses of these platforms require major attention to ensure effective outcomes.