Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors

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A few further observations from the American Society of Gene Therapy Meeting…


A recurrent theme in this blog is the frequency with which novel research fields encounter safety problems that confound laboratory predictions. One presentation at the 2009 ASGT meeting brought this point home.

Recall my entry on May 12 discussing various refinements to retroviral gene transfer that are aimed at reducing risk of malignancy. Researchers have postulated that HIV-derived lentiviral vectors might not cause the same leukemia-inducing mutations as retroviruses, and RAC recently passed a favorable judgment on a lentiviral vector gene transfer protocol for X-SCID.

How confident can we be that lentiviruses will not trigger leukemias? Some indication is provided in a May 2009 review by John Rossi in Molecular Therapy. It concluded “overall, the results of these [safety] analyses [of lentiviral vectors] are highly encouraging…” but “clearly, more careful analyses… are warranted in appropriate animal models.”

At ASGT, researchers from France reported preliminary results from a phase 1 trial testing lentiviral vectors in patients with beta-thalassemia. The study involved two patients. Though no malignancies have been detected, tests in one patient showed signs that some cells were repopulating the patients blood much faster than others (what researchers call “clonal dominance”). This is a worrisome signal, as it might indicate a premalignant state.

The lessons here are not that lentiviral vectors are unsafe (we don’t know whether this will lead to a malignancy), or that such vectors shouldn’t be used in human beings (we can’t say anything yet about the risk-benefit balance). Instead, I think the lesson is: in novel research areas, be very wary of anyone who makes emphatic claims that their system provides safe harbor. Expect the unexpected. (photo credit: dark matter, 2005)

BibTeX

@Manual{stream2009-95,
    title = {Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = jun,
    day = 23,
    url = {http://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/}
}

MLA

Jonathan Kimmelman. "Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors" Web blog post. STREAM research. 23 Jun 2009. Web. 25 May 2019. <http://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/>

APA

Jonathan Kimmelman. (2009, Jun 23). Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors [Web log post]. Retrieved from http://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/


Just the FACS: Reprise on Insertional Mutagenesis

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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).

BibTeX

@Manual{stream2008-123,
    title = {Just the FACS: Reprise on Insertional Mutagenesis},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = nov,
    day = 18,
    url = {http://www.translationalethics.com/2008/11/18/just-the-facs-reprise-on-insertional-mutagenesis/}
}

MLA

Jonathan Kimmelman. "Just the FACS: Reprise on Insertional Mutagenesis" Web blog post. STREAM research. 18 Nov 2008. Web. 25 May 2019. <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/


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