Two weeks ago brought good news and bad news for gene transfer. First the good news. New England Journal of Medicine beatified a new gene transfer strategy for Wiskott-Aldrich Syndrome (WAS). WAS is a primary immunodeficiency that primarily affects boys. It is thus in the same family of disorders that have been, in varying degrees, successfully addressed using retroviral gene transfer. Like other immunodeficiencies, this represents relatively low hanging fruit for an approach like gene transfer, because scientists can access and target stem cells, and because corrected cells should be at a selective advantage for survival compared with uncorrected cells.
The NEJM article reported clinical, functional, and molecular outcomes for two boys in a trial based in Germany. Briefly the two boys were given a type of chemotherapy (in order to make space for genetically corrected cells), and then transplanted with “corrected” blood stem cells. The corrected blood stem cells contained a viral vector similar to those used in previous gene transfer trials of primary immune deficiency. The team saw: 1) stable levels of genetically corrected stem cells that expressed the WAS protein (indicating the genetically modified cells “took,” and produced WAS; 2) recovery of the function of a variety of immune cells; 3) reduction of disease symptoms, including improvement of eczema, and reduced severity of infections.
The article exhaustively ruled out events that have occurred in other, similar gene transfer trials in which children developed leukemias from the vector. Now the bad news. The same day NEJM published the results, American Society of Gene and Cell Therapy (the largest professional society devoted to gene transfer) released a statement saying that the German team just announced “a serious adverse event in a gene therapy trial for Wiskott-Aldrich syndrome (WAS)”- one of the ten children in the German trial developed a leukemia.
And so continues the saga of gene transfer: three steps forward, one back. (photo credit: vk-red 2009)
@Manual{stream2010-58,
title = {Icarus, again: Adversity in another Gene Transfer Trial},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2010,
month = nov,
day = 29,
url = {http://www.translationalethics.com/2010/11/29/icarus-again-adversity-in-another-gene-transfer-trial/}
}
MLA
Jonathan Kimmelman. "Icarus, again: Adversity in another Gene Transfer Trial" Web blog post. STREAM research. 29 Nov 2010. Web. 29 Apr 2024. <http://www.translationalethics.com/2010/11/29/icarus-again-adversity-in-another-gene-transfer-trial/>
APA
Jonathan Kimmelman. (2010, Nov 29). Icarus, again: Adversity in another Gene Transfer Trial [Web log post]. Retrieved from http://www.translationalethics.com/2010/11/29/icarus-again-adversity-in-another-gene-transfer-trial/
Greetings after a hiatus for teaching, grants, committees, book deadlines, wiping runny noses, and more. Much has happened since my last posting, and in the next two or three weeks, I hope to catch up.
First item on the agenda is a Jan 29 report in New England Journal of Medicine (NEJM) describing successful reconstitution of immune function in eight of ten children receiving gene transfer for adenosine deaminase severe combined immune deficiency (ADA-SCID). The paper follows on a previous report in Science, 2002, and almost certainly counts as gene transfer’s greatest clinical accomplishment to date.
I have previously argued in Lancet and Developing World Bioethics, as well as in my forthcoming book, that this study raised important justice concerns because it recruited volunteers from economically disadvantaged settings without clearly fulfilling the requirement, articulated in the Declaration of Helinki, of responsiveness. The NEJM article does not say where subsequent volunteers were recruited, though the fact that all but one new volunteer received PEG-ADA (a very expensive standard of care available only in high-income countries) suggests that later patients were not economically disadvantaged.
Rather than dwell on justice, I’d like to focus on the significance of this study. As indicated, eight of ten children with a life threatening immune disorder had their immune systems reconstituted. Five of these children had T-cell counts that were “above the lower limits of normal.” These children were able to enjoy normal social relations parents and other children.
There do not appear to have been any adverse events relating to the gene transfer vector. A major concern was the possibility that gene transfer might trigger a leukemia-like syndrome observed in two X-SCID studies. Blood tests of children in this ADA-SCID study, however, do not evidence of either the leukemia syndrome or its precursors– at least within the time frame of the study (median follow-up of 4 years; range: 1.8-8 years).
So is ADA-SCID gene transfer ready to leave Milan and conquer ADA-SCID? For children lacking haplo-identical bone marrow donors, maybe so given the morbidity associated with marrow transplantation. Still, there are lingering concerns. First, though these results are encouraging, risks of malignancy remain unquantified. Second, this gene transfer regime requires several ancillary treatments- like bone marrow conditioning- that expose patients to risk of infection until the gene transfer intervention kicks in. Several volunteers in this study developed infections and neutropenia, for example. In an accompanying editorial in NEJM, Donald Kohn and Fabio Candotti describe several ways that retroviral gene transfer to blood stem cells might be made safer. Last, it is important to remember that ADA-SCID is a multi-system disorder, with neurological, skeletal, and other effects. Though this approach seems to address what is by far the largest cause of morbidity and mortality in children with ADA-SCID, it does eradicate their condition.
The results of Aiuti et al have been widely celebrated in the gene transfer community. Kohn and Candotti’s editorial, for example, is titled “Gene Therapy Fulfilling its Promise.” More than any single gene transfer study I can think of, this one seems to have earned the vindicating headlines. (photo credit: Paolo Margari, Milano Sazione Centrale Ferrovi, 2008)
@Manual{stream2009-109,
title = {Departing Milano Stazione? ADA-SCID and Gene Transfer},
journal = {STREAM research},
author = {Jonathan Kimmelman},
address = {Montreal, Canada},
date = 2009,
month = mar,
day = 10,
url = {http://www.translationalethics.com/2009/03/10/departing-milano-stazione-ada-scid-and-gene-transfer/}
}
MLA
Jonathan Kimmelman. "Departing Milano Stazione? ADA-SCID and Gene Transfer" Web blog post. STREAM research. 10 Mar 2009. Web. 29 Apr 2024. <http://www.translationalethics.com/2009/03/10/departing-milano-stazione-ada-scid-and-gene-transfer/>
APA
Jonathan Kimmelman. (2009, Mar 10). Departing Milano Stazione? ADA-SCID and Gene Transfer [Web log post]. Retrieved from http://www.translationalethics.com/2009/03/10/departing-milano-stazione-ada-scid-and-gene-transfer/
