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Recombinant DNA Technology and Gene Therapy Using Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
LUXTURNA is a type of gene therapy used for patients with “retinal dystrophy” caused by mutations in RPE65. The specific disease involved is also known as Leber congenital amaurosis, which causes a deterioration of the retina leading to blindness. The drug was approved for use in 2017 and was the first in vivo gene therapy approved using an AAV vector (AAV2) in the United States (Anguela and High 2019; Russell et al. 2017; Ledford 2015; Wang, Tai, and Gao 2019; Dunbar et al. 2018; Li and Samulski 2020; Shahryari et al. 2019).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In another example, voretigene neparvovec (LuxturnaTM), developed by Spark Therapeutics Inc, is a gene therapy used to treat adults and children with loss of vision due to inherited retinal dystrophy, a rare genetic disorder of the retina. Approved in 2018, LuxturnaTM can only be used while patients still have enough functioning cells left in the retina and when the disease is caused by mutations in the RPE65 gene responsible for production of the enzyme, all-trans retinyl isomerase, necessary for the normal functioning of retinal cells. The key point is that LuxturnaTM is injected directly (sub-retinally) into the eye, thus avoiding any systemic off-target effects which would not be the case for cancer therapies. Other applications of gene therapy approaches such as the treatment of human immunodeficiency virus (HIV) infections and correction of the mutation that causes sickle cell disease may soon become a reality.
Challenges Facing the American Healthcare System
Published in Kant Patel, Mark Rushefsky, Healthcare Politics and Policy in America, 2019
In 2017 the FDA approved three gene therapies to enter the market. One is Luxturna, which is a virus vector-based therapy for the treatment of patients with retinal dystrophy. The other two are CAR T-Cell therapies—Kymriah to treat leukemia and Yescarta to treat lymphoma (Weintraub 2018). This new pioneering cancer drug therapy, called CAR T-Cell, is made by harvesting patients’ white blood cells and rewiring them to hone in on tumors. This therapy has produced unprecedented success in patients with rare and deadly cancers (McGinley 2017; Patel 2017). The price tag is $475,000 for a course of treatment (Garde 2017). The cost of first gene therapy for an inherited disorder—a rare condition that causes a progressive form of blindness that usually starts in childhood—is estimated to be around $1 million for each treatment (Stein 2017).
Emerging gene therapy products for RPGR-associated X-linked retinitis pigmentosa
Published in Expert Opinion on Emerging Drugs, 2022
Cristina Martinez-Fernandez de la Camara, Jasmina Cehajic-Kapetanovic, Robert E. MacLaren
In addition, Luxturna®, the first approved gene therapy for another inherited retinal degeneration, has set a precedent for other trials. The success was due to a better clinical and scientific understanding of safety profiles of the gene therapy vector. The regulatory approval also included recognition of the AAV vector manufacturing process that met the quality standards required for clinical scale production. The trial endpoint was an improvement in visual function with no obligation to demonstrate a slowing of retinal degeneration, which would have taken many years to validate and which would not be practical for a company to undertake. Spark Therapeutics, which ran the trial, was able to demonstrate to the authorities that another new test (multi luminance mobility test) could provide a meaningful Phase III trial endpoint, in place of traditional outcomes, such as visual acuity. Similarly, following successes of Phase I/II RPGR clinical trials [30], Biogen was able to show the authorities that retinal sensitivity as measured by microperimetry can be used as the primary endpoint for Phase III efficacy trial. It must be emphasized that potential participants must be familiar with these new investigative techniques and able to perform tests accurately to ensure reliable detection of potential treatment effects.
Newer therapeutic agents for retinal diseases
Published in Expert Review of Ophthalmology, 2022
Ashish Markan, Swechya Neupane, Rupesh Agrawal, Vishali Gupta
With FDA approval of Luxturna for RPE 65 mediated inherited retinal diseases; the research in the field of gene therapy has accelerated. Different delivery methods (lentivirus, adeno-associated virus), injection sites (intravitreal, subretinal, suprachoroidal), and methodologies (gene replacement,, editing, silencing) are currently being tested [7]. There are several challenges associated with gene therapy. IRDs being a rare group of eye disorders and associated with over 200 different genes implicated, it is difficult to recognize potential candidates for a particular gene therapy. It is also important that patients be identified at an early stage of disease, so that they have some viable retinal cells which can be targeted. Safety issues are another concern associated with gene therapy. Available gene therapies require a surgical procedure like pars plana vitrectomy and delivery of gene therapy in subretinal space. This poses the patients to additional risk of complications associated with these surgical procedures. Lastly, high financial cost associated with gene therapy at present will definitely make this treatment option inaccessible to many.
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.