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/}
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MLA
Jonathan Kimmelman. "Icarus, again: Adversity in another Gene Transfer Trial" Web blog post. STREAM research. 29 Nov 2010. Web. 05 Dec 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/
Among the greatest heartbreaks in the field of gene transfer have been problems encountered in trials involving a rare, hereditary immune disorder, X-SCID (known popularly as “Bubble Boy” syndrome). As is well known, a team of researchers based in Paris– and then in London– successfully reversed severe immunodeficiencies in 20 or so children using retroviral gene transfer starting around year 2000. Shortly thereafter, however, the Paris team began observing rare leukemic disorders that were causally related to the gene transfer. To date, the Paris team has reported 4 cases of leukemia, with one leading to death. The London team has reported one leukemia.
In response to these events, the U.S. Recombinant DNA Advisory Committee (RAC) recommended that investigators only use retroviral gene transfer in the most severe situations– namely, where patients are ineligible for even high risk alternative care options like haploidentical stem cell transplantation. RAC’s recommendations were stricter than those in the U.K., which allowed children to enter a study even if they were candidates for haploidentical transplants.
As reported in the current issue of Molecular Therapy, the RAC recently decided to liberalize its recommendations, allowing retroviral gene transfer in children who are eligible for halploidentical transplantation. RACs recommendations are still somewhat stricter than those of the UK, because the former recommends against retroviral gene transfer in children who are candidates for haploidentical transplantation but under 3.5 years age (children in this category respond better to haploidentical transplants). RAC additionally supported a similar trial involving a different vector that integrates its genome into the host’s (lentiviral vectors, which are derived from HIV).
Is this gentle liberalization of standards justified? Some will argue that the benefits of haploidentical transplantation are variable and undependable, and that since initial leukemias have been reported, researchers have made progress in improving the safety of their vectors. All this might be true, if one were evaluating this as a clinical judgment.
However, the judgment is better viewed through the lens of research rather than therapy. Though laboratory testing indicates that new retroviral and lentiviral vectors are safer than the old ones, there remain substantial uncertainties. For example, current assays for determining the oncogenicity of integrating vectors are not well worked out. Neither the new retroviral vectors nor lentiviral vectors have been used in blood stem cell gene transfer in a pediatric population. The effect of lentiviral vectors on gene sequences near their integrating sites remains poorly understood. In short, the null hypothesis of new trials is that these new vectors are no better than the old ones.
What’s the safest way to refute this null hypothesis and confirm what many think, on laboratory evidence, will be the case? In my view, the safest approach– for patients as well as the field in general, which stands to lose much from another major toxicity– is to begin with the most narrow medical indication possible, which means excluding children who stand a chance of benefiting from standard (albeit suboptimal) care. (photo credit: Jamelah 2007)
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MLA
Jonathan Kimmelman. "Yellow Light on Gene Transfer Studies" Web blog post. STREAM research. 12 May 2009. Web. 05 Dec 2024. <http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/>
APA
Jonathan Kimmelman. (2009, May 12). Yellow Light on Gene Transfer Studies [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/
Further to the therapeutic outlook on first-in-human studies at the Brugge meeting was Adrian Thrasher’s thoughtful presentation on his own X-SCID study at Great Ormand Street Hospital. Thrasher’s study was able to restore immune function in nearly all volunteers. Recently, however, his team reported a lymphoproliferative disorder like those seen in a very similar Paris study.
Thrasher stated clearly “The purpose [of X-SCID protocol] is therapeutic effect; it is not a safety study.” Fair enough: the study was in a pediatric population (standard research ethics requires clear therapeutic warrant for such risky studies), and Thrasher’s protocol did not range doses the way typical first-in-human studies do. And I should add, there is some grounds for thinking of the study as having therapeutic warrant, not the least because it was supported several unsuccessful X-SCID human studies and a successful one in Paris). Still, putting the therapy before the learning- this made me somewhat uncomfortable. Therapy might have been his (and his hospital’s) intent, but to describe the study as ontologically “therapeutic” and not “research”? Intent only gets us so far…
Thrasher revealed some unusual properties about the molecular events leading to this leukemia (see? told you it could be construed as a safety study). And now, here’s the compassion part. Thrasher was circumspect about this particular leukemia, because the patient who developed the leukemia had originally been ineligible for the protocol because he had a matched unrelated bone marrow donor. The regulatory agency made a “one-time” exception to waive the normal risk-benefit balance.
Of course, one should be very careful generalizing from this one case where “compassion” seems to have led authorities astray. And presumably, the boy’s parents were thoroughly informed about the risks going in to the protocol. Still, the example is somehow instructive. (photo credit: missinguigga 2008).
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title = {In Brugge / No Compassion (Part II)},
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MLA
Jonathan Kimmelman. "In Brugge / No Compassion (Part II)" Web blog post. STREAM research. 29 Nov 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/11/29/in-brugge-no-compassion-part-ii/>
APA
Jonathan Kimmelman. (2008, Nov 29). In Brugge / No Compassion (Part II) [Web log post]. Retrieved from http://www.translationalethics.com/2008/11/29/in-brugge-no-compassion-part-ii/
I‘ve just returned from the annual European Society of Gene and Cell Therapy meeting in Belgium. Lots of great material for upcoming posts. For now, I want to follow on the last posting on the leukemias in the X-SCID study. A warning: those lacking a stomach for science geek-talk might want to skip this posting.
In the previous posting, I stated that a recent paper provided evidence that retroviral integration in the genome (“insertional mutagensis”) had triggered leukemias in the X-SCID study rather than over-expression of the corrective gene (“transgene”), the gamma c-chain (hereafter, “gc”). This was on the basis of data in the graphic above, which used cell sorting to show that levels of gc on the surface of T-cells was within a normal range. In Belgium, Adrian Thrasher presented similar data for the fifth leukemia.
When I first encountered this figure, it bothered me: why did the authors measure gc expression by cell surface markers (a technique called “FACS”) rather than Western or Northern blotting, or quantitative PCR, or something along these lines? It seemed a very indirect way of seeing whether gc expression levels are in fact normal. Here are two possibilities that this figure fails to rule out: 1- gc is expressed at very high levels, but not packaged and presented on the surface of T-cells, perhaps because of insufficiency of other receptor components; 2- some gc transgene is aberrantly spliced, such that surface levels are normal, but intracellular concentrations of the alternate splicing product are abnormal.
A few years back, one team of researchers presented data indicating that gc transgene overexpression contributes to T-cell transformation. Another team claimed it was unable to reproduce this. The jury seems to still be out on whether the gc product contributed to the X-SCID leukemias, and I’m not yet convinced that the latest round of data fully exonerates the gc chain. (Graphic: figure from Salima Hacein-Bey-Abina et al, J Clinical Investigation 2008; 108: 3132-42).
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title = {Just the FACS: Reprise on Insertional Mutagenesis},
journal = {STREAM research},
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url = {http://www.translationalethics.com/2008/11/18/just-the-facs-reprise-on-insertional-mutagenesis/}
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MLA
Jonathan Kimmelman. "Just the FACS: Reprise on Insertional Mutagenesis" Web blog post. STREAM research. 18 Nov 2008. Web. 05 Dec 2024. <http://www.translationalethics.com/2008/11/18/just-the-facs-reprise-on-insertional-mutagenesis/>
APA
Jonathan Kimmelman. (2008, Nov 18). Just the FACS: Reprise on Insertional Mutagenesis [Web log post]. Retrieved from http://www.translationalethics.com/2008/11/18/just-the-facs-reprise-on-insertional-mutagenesis/
