More on Lenti’s, Gene Transfer and Adrenoleukodystrophy

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(…continued from the previous post). There are several features that make the recent Adrenoleukodystrophy (ALD) gene transfer study noteworthy.


1- A New Viral Vector Debuts: this is the first successful application of HIV-derived viruses in gene transfer (lentiviruses). These vectors have various advantages over retroviruses used in other protocols. One is that, in theory, at least, they are supposed to be safer. Previous trials of the same team (different disease) involving retroviruses triggered leukemia-like disorders in several volunteers. In this study, the authors do not detect any evidence that cells are poised to cause a malignancy. However, in a post this summer, I noted that another trial involving thalessemia and lentiviruses did, indeed, detect clonal enrichment. And the ALD study enrolled only two patients- if there were going to be safety problems detected, they’d need to be massive to be detected in so small a sample of patients. Thus, despite the encouraging findings in the ALD study, the safety of lentiviral gene transfer remains to be firmly established.

2- Prior Animal and Clinical Experience are Successfully Integrated: here is one instance where favorable clinical outcomes were achieved on the basis of limited preclinical evidence. Specifically, the authors previously tested their approach in mice, but because rodents do not develop the same pathology as human beings, they were uncertain whether the gene correction would be sufficient to correct the disorder in human patients. These animal studies were bootstrapped with extensive experience with bone marrow transplantation in children with ALD. Rarely is this transition from rodents into clinical applications so successful. All the more surprising- this is occurring within the realm of central nervous system disorders, which have a particularly high rate of failed drug development.

3- Patients in the Service of Science: This study will no doubt be perceived as a story of “science in the service of patients:” a team of clinicians applying cutting edge discoveries to do the best they can for their patients. But it is as much- perhaps more- a story of patients in the service of science. The study is notable for how well it used the occasion of ALD to make more fundamental discoveries. For example, in a “Perspective” piece that accompanies the published trial, Luigi Naldini describes this as what “may be a first glimpse of live [generation of new blood and immune cells at the level of DNA].” Naldini also notes how the study developed and applied new techniques for ruling out clonal dominance that “will likely become a gold standard.” Also intriguing is the hint that this approach may be applicable for other disorders involving the central nervous system, and the finding that only a small amount of gene correction is needed to arrest the pathology. (photo credit: photobunny 2007)

BibTeX

@Manual{stream2009-78,
    title = {More on Lenti’s, Gene Transfer and Adrenoleukodystrophy},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 12,
    url = {http://www.translationalethics.com/2009/11/12/more-on-lentis-gene-transfer-and-adrenoleukodystrophy/}
}

MLA

Jonathan Kimmelman. "More on Lenti’s, Gene Transfer and Adrenoleukodystrophy" Web blog post. STREAM research. 12 Nov 2009. Web. 15 Jul 2019. <http://www.translationalethics.com/2009/11/12/more-on-lentis-gene-transfer-and-adrenoleukodystrophy/>

APA

Jonathan Kimmelman. (2009, Nov 12). More on Lenti’s, Gene Transfer and Adrenoleukodystrophy [Web log post]. Retrieved from http://www.translationalethics.com/2009/11/12/more-on-lentis-gene-transfer-and-adrenoleukodystrophy/


Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris

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Last week’s Science magazine reported what seems likely to count as one of gene transfer’s greatest clinical successes to date: stabilization of adrenoleukodystrophy in two boys receiving genetically modified blood stem cells. Preliminary results of this study had been presented at this summer’s American Society of Gene and Cell Therapy meeting.


Adrenoleukodystrophy (ALD) is a rare hereditary brain disorder in which a deficiency in a gene, ABCD1, causes degeneration of tissues (myelin) that insulate cells in the central nervous system. The disease is familiar to many because of its most famous patient, Lorenzo Odone, whose story was featured in the movie Lorenzo’s Oil. Untreated, ALD is invariably fatal.

Because myelin cells originate from blood stem cells, researchers had previously used bone marrow transplantation to successfully halt progression of demyelination in ALD patients. However, bone marrow transplantation has two severe limitations: many patients lack matched bone marrow donors; second, even when a matched donor is available, the procedure is burdensome and risky.

In this most recent study, researchers at Hôpital Necker in Paris transplanted genetically modified bone marrow cells into two Spanish boys who lacked matched bone marrow donors. The boys were also given myeloablative conditioning- a type of chemotherapy that increases the likelihood that genetically modified cells will repopulate the bone marrow. The Science report showed:

1- genetically modified cells did, indeed, survive and were maintained at stable levels for two years.
2- the modified cells expressed the therapeutic gene, ABCD1, again for two years.
3- brain demyelination was halted after 14 months- the timing is similar to what would occur for patients receiving bone marrow transplantation.
4- the two boys did not appear to decline on various measures of neurological or verbal tests, as would almost certainly have occurred with the natural course of ALD.
5- the authors did not detect “clonal dominance” in their modified cells– that is, evidence that genetically modified cells were poised to cause a malignancy.

In an accompanying editorial, Luigi Naldini calls this study a “Comeback for Gene Therapy,” describing it as a “long-sought rewarding achievement in the field of gene therapy.” In my next post, I will discuss some implications, interpretations, and other interesting dimensions of this very encouraging study (photo credit: tgif28, chalk graffiti at Hopital Necker, 2009)

BibTeX

@Manual{stream2009-79,
    title = {Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = nov,
    day = 12,
    url = {http://www.translationalethics.com/2009/11/12/gene-transfer-and-adrenoleukodystrophy-there-will-always-be-paris/}
}

MLA

Jonathan Kimmelman. "Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris" Web blog post. STREAM research. 12 Nov 2009. Web. 15 Jul 2019. <http://www.translationalethics.com/2009/11/12/gene-transfer-and-adrenoleukodystrophy-there-will-always-be-paris/>

APA

Jonathan Kimmelman. (2009, Nov 12). Gene Transfer and Adrenoleukodystrophy: There Will Always Be Paris [Web log post]. Retrieved from http://www.translationalethics.com/2009/11/12/gene-transfer-and-adrenoleukodystrophy-there-will-always-be-paris/


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