Yellow Light on Gene Transfer Studies

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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)

BibTeX

@Manual{stream2009-103,
    title = {Yellow Light on Gene Transfer Studies},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = may,
    day = 12,
    url = {http://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/}
}

MLA

Jonathan Kimmelman. "Yellow Light on Gene Transfer Studies" Web blog post. STREAM research. 12 May 2009. Web. 21 Sep 2017. <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/


Centralized Revue

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In the most recent issue of Molecular Therapy, U Penn researcher Hildegrund Ertl provides a strong and eloquent defense of the Recombinant DNA Advisory Committee (RAC).  RAC was initially formed to evaluate the safety of studies involving recombinant DNA. In the last decade, however, its most visible function has been to provide advise to researchers pursuing novel gene transfer protocols in human beings.


Many researchers resent RAC, viewing it as yet another layer of oversight for their clinical studies. Understandably, they question whether it makes sense to have a separate review track for gene transfer. Other scientists and ethicists might question whether gene transfer is so exceptional as to be singled out for separate review, but would nevertheless argue that the RAC model should be extended to other ethically contentious areas of medical research. Nevertheless, the RAC model of centralized review of trial protocols has yet to be extended to comparably novel and contentious human clinical research areas like cell transfer, embryonic stem cell research, or tissue engineering.

Ertl provides a clear and persuasive description of RAC’s role in improving gene transfer trial safety, enhancing scientific value of studies, and ensuring appropriate informed consent practices. But the structure of her argument embeds three assumptions that, in my view, need to be questioned.

1- Why demand solid preclinical evidence? Ertl answers “if such data are not available, the risk outweighs the potential benefit for human volunteers– and that is not acceptable.” I would argue that preclinical evidence is of greater use in improving the scientific value of clinical studies. 

2- How are risks justified in early phase studies? In the above quote, Ertl seems to suggest the answer is therapeutic benefit for the volunteer. In my view, risks in first-in-human trials are justified by the potential for scientific gain, not direct medical benefit.

3- What is the purview of ethics? Ertl, like many others, partitions “technical” concerns like study validity / value / preclinical evidence from “ethical” concerns like informed consent and conflict of interest. But why is the former any less ethical than the latter, given that technical questions implicate problems of risk-benefit balance and the ultimate ends of research. In my view, there is no clear division between the technical and ethical, and few if any decisions in designing and executing clinical protocols are devoid of ethical content. (photo credit: 416style, 2005)

BibTeX

@Manual{stream2009-108,
    title = {Centralized Revue},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = mar,
    day = 27,
    url = {http://www.translationalethics.com/2009/03/27/centralized-revue/}
}

MLA

Jonathan Kimmelman. "Centralized Revue" Web blog post. STREAM research. 27 Mar 2009. Web. 21 Sep 2017. <http://www.translationalethics.com/2009/03/27/centralized-revue/>

APA

Jonathan Kimmelman. (2009, Mar 27). Centralized Revue [Web log post]. Retrieved from http://www.translationalethics.com/2009/03/27/centralized-revue/


From Bench to Ringside: The Presidential Debate

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Last night, Obama and McCain confronted each other in the final Presidential debate. A flagging economy and two wars have left little room in the two campaigns for discussion of science, policy, and human research. Yet last night’s debate touched on two themes: embryonic stem cell (hES) research, and biomedical research funding.


Obama accused McCain of opposing embryonic stem cell research. From what I can tell, McCain actually supported the use of embryonic tissue for research and opposed Bush’s ban and vetoes. But the logic of McCain’s attacks on Obama, of late, are that personal associations tell us something about who a person is and where they stand. And McCain pals around with embryo research opponents like his running mate.

Contrast the two candidates’ statements on hES research from Sciencedebate 2008– a group that invited McCain and Obama to declare positions on various science policy issues. McCain stated “While I support federal funding for embryonic stem cell research, I believe clear lines should be drawn….”  The remainder of his response qualifies his support.  On his own website, McCain stops short of declaring support–or opposition– for hES research, and talks more about what he would oppose than what he would support.  Obama’s support is more full-throated at Sciencedebate 2008: “As president, I will lift the current administration’s ban on federal funding of research on embryonic stem cell lines… embryonic stem cells remain the ‘gold standard,’ and studies of all types of stem cells should continue in parallel for the foreseeable future.”

Elsewhere at Sciencedebate 2008, Obama’s campaign singled out gene transfer in a statement on genetics: “As a result [of safety issues involving ‘gene therapy’], the NIH established the Recombinant DNA Advisory Committee…. Until we are equipped to ascertain the safety of such methods, I will continue to support the activities and recommendations of the Recombinant DNA Advisory Committee.” [Note: Harold Varmus chairs a science advisory committee for the Obama campaign. Varmus reorganized RAC when he was the director of the NIH under the Clinton administration]

What about research– specifically translational research?  Just as they do for Joe the plumber, both candidates support NIH research. According to a report in Science (“Scientists Strive for a Seat at the Table of Each Campaign,” Jeffrey Mervis, 26 Sept), Obama pledged to double the NIH budget in five years. Elsewhere, his campaign said 10 years. Maybe the latter figure is inflation adjusted? Obama’s statement on Science and Innovation singles out “rapid translation of medical research.”

I am not aware of any clear statements on translational research from McCain, though he favors greater funding for NIH, and based on his debate and website, he seems to have a soft spot for autism research. As on other issues, McCain is less willing to commit to a timetable on NIH budget doubling. (photo credit: Thomas Hawk, Wordle of McCain and Obama convention speeches, 2008)

BibTeX

@Manual{stream2008-129,
    title = {From Bench to Ringside: The Presidential Debate},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = oct,
    day = 16,
    url = {http://www.translationalethics.com/2008/10/16/from-bench-to-ringside-the-presidential-debate/}
}

MLA

Jonathan Kimmelman. "From Bench to Ringside: The Presidential Debate" Web blog post. STREAM research. 16 Oct 2008. Web. 21 Sep 2017. <http://www.translationalethics.com/2008/10/16/from-bench-to-ringside-the-presidential-debate/>

APA

Jonathan Kimmelman. (2008, Oct 16). From Bench to Ringside: The Presidential Debate [Web log post]. Retrieved from http://www.translationalethics.com/2008/10/16/from-bench-to-ringside-the-presidential-debate/


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