Deaths from Gene Therapy

choi

(1) Jesse Gelsinger
(a) Sibbald B, Death But One Unintended Consequence of Gene-Therapy Trial. CMAJ (short for Canadian Medical Association Journal), 164: 1612 (2001)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81135/
("the 18-year-old American became the first person [in the world] to die because of participation in gene-therapy research.  [Jesse] Gelsinger had ornithine transcarbamoylase (OTC) deficiency, a metabolic disorder that affects 1 in 40 000 newborns by impeding the elimination of ammonia. * * * Gelsinger's outcome was different because he had only partial OTC deficiency, which he kept in check with a low-protein diet and drugs. He was considered an ideal candidate for the trial, led by Dr James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania.  On Sept 13, 1999, Gelsinger was given an infusion of corrective OTC gene encased in a dose of attenuated cold virus, a recombinant adenoviral vector; it was injected into his hepatic artery. Gelsinger experienced a severe immune reaction to the vector — the gene's delivery vehicle — and died 4 days after receiving the injection")
(i) Jesse Gelsinger's OTC deficiency is a "somatic mosaic mutation," meaning that the mutation in the OTC occurs sometimes AFTER fertilization, so that some cells (but not others) in his body has the mutation at issue.
(ii) Most people are once infected with adenovirus (causing flu-like symptoms) and hence have developed antibody, but Gelsinger's antibody (against adenovirus) was exceptionally strong.
(iii) Because of his death, adeno-associated viruses (AAV) rather than adenovirus is used as a vector (the protein coat of a virus -- or capsid in virology). Oftentimes, AAV vector does not bring about integration (into host genome), which nonetheless may still occur -- and causes animals to develop cancers in experiments.
(iv) urea cycle
https://en.wikipedia.org/wiki/Urea_cycle
(takes place primarily in the liver; the only figure shows a mitochondrion (whose plural is mitochondria, being Latin) at the top and cytosol below, of a liver cell, say)
(A) carbamoyl phosphate + ornithine ---OTC--> citrulline
(B) carbamic acid
https://en.wikipedia.org/wiki/Carbamic_acid
(section 2 Derivatives of carbamic acid: carbamoyl group)

carbamic acid (n; etymology: International Scientific Vocabulary carbamide [which is another name for urea) + -ic)
https://www.merriam-webster.com/dictionary/carbamic%20acid
(C) ornithine (n; etymology)
https://www.merriam-webster.com/dictionary/ornithine
(D) "Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated in 1914 by Koga and Odake."  en.wikipedia.org for citrulline.

The Japanese researcher's surname Odake is misspelled; it should be be Yotarō KOGA 古賀 弥太郎 and Ryō ŌTAKE (some papers spell it OHTAKE) 大嶽 了. See
Konstantinos C Frakos and Alastair Forbes, Was Citrulline First a Laxative Substance?: The Truth about Modern Citrulline and Its Isolation. Journal of the Japanese Society for the History of Medicine 日本医史学雑誌 (published by 日本医史学会), 57: 275 (2011), at page 278
https://jsmh.umin.jp/journal/57-3/57-3_275.pdf
("The first isolation of citrulline occurred in 1914 by Yotaro Koga and Ryo Ohtake, who isolated citrulline from the juice of the watermelon") (citation omitted)

(2)
(a) Hacein-Bey-Abina S et al, Insertional Oncogenesis in 4 Patients After Retrovirus-Mediated Gene Therapy of SCID-X1. 118: 3132 (2008).
https://www.ncbi.nlm.nih.gov/pubmed/18688285
(Paris reports that of the 4 cases who developed T cell leukemia -- besides 2 cases reported in 2003 that LIM2 underlined, but was not the only mutations of,leukemia -- in 2 others, one had integrations near both LMO2 and BMI1 whereas the other had integration near CCND2 gene [for protein CyCliN D2])
(b) Howe SJ et al, Insertional Mutagenesis Combined with Acquired Somatic Mutations Causes Leukemogenesis Following Gene Therapy of SCID-X1 Patients. J Clin Invest, 118: 3143
https://www.ncbi.nlm.nih.gov/pubmed/18688286
(University College London reports "occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by * * * Integration of the vector in an antisense orientation 35 kb upstream of the protooncogene LIM domain only 2 (LMO2) caused overexpression of LMO2 in the leukemic clone")