Phase 1 gene transfer trial for ornithine transcarbamylase deficiency (13–17)
Ornithine transcarbamylase (OTC) deficiency is an inherited genetic disease that affects the urea cycle in the liver. As a result, high levels of ammonia accumulate in the body and damage the nervous system. Because the OTC gene is found on the X-chromosome, most of the patients are male. Females often have little or no symptoms.
The severity of this disease also depends on the type of defect in the OTC gene. Those who have a serious defect in the gene may experience seizures and coma within the first few days of birth. Even if they survived this neonatal crisis, many develop severe cognitive decline and die in childhood. Liver transplant is an option for children who are stabilised by strict diet and medical therapy.
On the other hand, those with only partial defect of the OTC gene may live normally as adults and only experience occasional mild symptoms such as delirium. (15,16)
In the early 1990s, researchers from the University of Pennsylvania developed a technique to transfer a functioning OTC gene into the liver. At the time, this method was the first of its kind. Pre-clinical studies were promising and the researchers wanted to conduct a first-in-human study. (13)
The main purpose of this phase 1 study was to determine the ‘safety, feasibility and potential efficacy’ (ClinicalTrials.gov, 1999) of this novel gene transfer technique.
Wilson JM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Molecular Genetics and Metabolism. 2009 Apr 1;96(4):151–7. Available from: http://www.sciencedirect.com/science/article/pii/S109671920800499X
ClinicalTrials.gov. Phase I Study of Adenoviral Vector Mediated Gene Transfer for Ornithine Transcarbamylase in Adults With Partial Ornithine Transcarbamylase Deficiency [Internet]. NIH U.S. National Library of Medicine. 1999 [cited 2019 Jan 9]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT00004498
Genetics Home Reference. Ornithine transcarbamylase deficiency [Internet]. NIH U.S. National Library of Medicine. [cited 2019 Jan 9]. Available from: https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency
Recombinant DNA Advisory Committee. Minutes of Symposium and Meeting, December 8-10, 1999 [Internet]. U.S. Department of Health and Human Services, National Institute of Health; 1999. Available from: https://osp.od.nih.gov/wp-content/uploads/2014/01/1299rac.pdf
Steinbrook R. The Gelsinger Case. In: The Oxford Textbook of Clinical Research Ethics [Internet]. 1st ed. New York: Oxford University Press; 2011. p. 110–20. Available from: https://www.uab.edu/ccts/images/steinbrook_Gelsinger_-_Oxford_Textbook_08_3.pdf
Genetics Home Reference. Ornithine transcarbamylase deficiency [Internet]. NIH U.S. National Library of Medicine. [cited 2019 Jan 9]. Available from: https://ghr.nlm.nih.gov/condition/ornithine-transcarbamylase-deficiency
Recombinant DNA Advisory Committee. Minutes of Symposium and Meeting, December 8-10, 1999 [Internet]. U.S. Department of Health and Human Services, National Institute of Health; 1999. Available from: https://osp.od.nih.gov/wp-content/uploads/2014/01/1299rac.pdf
Wilson JM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Molecular Genetics and Metabolism. 2009 Apr 1;96(4):151–7. Available from: http://www.sciencedirect.com/science/article/pii/S109671920800499X
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