(…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)
@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 = {https://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. 24 Apr 2024. <https://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 https://www.translationalethics.com/2009/11/12/more-on-lentis-gene-transfer-and-adrenoleukodystrophy/
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)
@Manual{stream2009-95,
title = {Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors},
journal = {STREAM research},
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month = jun,
day = 23,
url = {https://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/}
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MLA
Jonathan Kimmelman. "Safe Harbor? Leukemia, Gene Transfer, and Lentiviral Vectors" Web blog post. STREAM research. 23 Jun 2009. Web. 24 Apr 2024. <https://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 https://www.translationalethics.com/2009/06/23/safe-harbor-leukemia-gene-transfer-and-lentiviral-vectors/
@Manual{stream2009-97,
title = {Clonal Trouble},
journal = {STREAM research},
author = {Jonathan Kimmelman},
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date = 2009,
month = may,
day = 29,
url = {https://www.translationalethics.com/2009/05/29/clonal-trouble/}
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MLA
Jonathan Kimmelman. "Clonal Trouble" Web blog post. STREAM research. 29 May 2009. Web. 24 Apr 2024. <https://www.translationalethics.com/2009/05/29/clonal-trouble/>
APA
Jonathan Kimmelman. (2009, May 29). Clonal Trouble [Web log post]. Retrieved from https://www.translationalethics.com/2009/05/29/clonal-trouble/
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)
@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 = {https://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. 24 Apr 2024. <https://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 https://www.translationalethics.com/2009/05/12/yellow-light-on-gene-transfer-studies/
