More Gray Matter: Parkinson’s Disease and Gene Transfer

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Several groups are pursuing gene transfer strategies against Parkinson’s disease. No small task, because for these approaches to work, investigators have to deliver vectors deep inside the brain using surgery. I have previously written that early phase studies using surgical delivery press the boundaries of acceptable risk, because patients can generally manage their disease adequately- though far from completely- with dopamine replacement, and study participation entails nontrivial surgical risks (by my calculations, about 0.5% chance of mortality, depending on the approach).


In the December issue of Lancet Neurology, Marks et al report results of a phase 2, sham controlled trial of CERE-120. The results were negative. That is, for the main measure in the study, improvement in symptoms at 12 months, patients receiving CERE-120 did not do significantly better than patients receiving sham. On the other hand, the product did not raise any major safety issues, apart from a hemorrhage during surgery in one patient.

The team performing the study has emphasized several “positive” outcomes. For one, patients receiving CERE-120 generally responded better than patients in the sham arm (though not significantly better- that is, differences may be attributable to chance). And on a secondary endpoint- response at 18 months- patients receiving CERE-120 did indeed perform significantly better. So did Ceregene score against Parkinson’s disease? In an accompanying commentary, French Neurologist Alim Benabid says “the findings… provide the first clinical evidence of a clinical benefit of gene therapy in Parkinson’s disease.”

I ain’t no neurologist, but I say: hold on a minute. When researchers start trials, they pick primary endpoints based on where they think they are most likely to succeed. In this case, the researchers picked improvement at 12 months, rather than at 18 months. From the looks of it, they backed the wrong horse- patients did significantly better at 18 rather than 12 months. What does this tell us? Success in a secondary endpoint might have occurred by chance, and the fact that researchers were unsuccessful on their primary endpoint indicates that they do not yet understand enough about their system to pick the “right” endpoints. So I see this as symptomatic of scientific uncertainty rather than a glimpse of medical destiny. [[One other issue to consider: it is possible that surgery itself (rather than gene transfer) may have caused symptomatic improvements.]]

The study was well reported and provides, yet again, evidence of the utility of sham comparator arms in studies involving Parkinson’s disease. One disappointing feature, however, is that the authors did not report whether patients or clinicians could correctly guess their treatment allocation just prior to unblinding. Without this, it is difficult to exclude the possibility that any difference between groups- even at 18 months- was due to “placebo effect.” (photo credit: Vin6, 2007)

2010 December 20 | Leave a comment | Tags:

BibTeX

@Manual{stream2010-57,
    title = {More Gray Matter: Parkinson’s Disease and Gene Transfer},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = dec,
    day = 20,
    url = {http://www.translationalethics.com/2010/12/20/more-gray-matter-parkinsons-disease-and-gene-transfer/}
}

MLA

Jonathan Kimmelman. "More Gray Matter: Parkinson’s Disease and Gene Transfer" Web blog post. STREAM research. 20 Dec 2010. Web. 05 Dec 2024. <http://www.translationalethics.com/2010/12/20/more-gray-matter-parkinsons-disease-and-gene-transfer/>

APA

Jonathan Kimmelman. (2010, Dec 20). More Gray Matter: Parkinson’s Disease and Gene Transfer [Web log post]. Retrieved from http://www.translationalethics.com/2010/12/20/more-gray-matter-parkinsons-disease-and-gene-transfer/

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Icarus, again: Adversity in another Gene Transfer Trial

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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)

2010 November 29 | Leave a comment | Tags:

BibTeX

@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/}
}

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/

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Ark, Troubled Waters, and Rainbows for Gene Transfer

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This morning I awoke to a news report by National Public Radio’s Joe Palca on promising developments in gene transfer. In it, Palca provided a good account of the field’s travails, as well as some encouraging developments in the last few years. The story ended with the prediction that the coming “months and years” would bring landings for more common disorders like AIDS and cancer.


Coincidentally, the just released March issue of Nature Biotechnology ran a report on a front-runner for gene transfer commercialization: biotechnology company Ark Therapeutics gene transfer gliobastoma product Cerepro. The application for licensure of this product in Europe was unsuccessful (press release here). Recall that, last June, I described what seemed like unimpressive results from a phase 3 trial that were reported at an annual meeting of the American Society of Gene Therapy. Apparently, European drug regulators weren’t impressed either (they cited flaws in trial design, including a small sample size and unconcealed allocation; Ark has asked the agency to re-examine their application).

But for those awaiting the first commercialization of a gene transfer product in a country with a robust drug regulatory system, there is still some indication that the rains may be subsiding: according to the report in Nature Biotechnology, Amsterdam Molecular Therapeutics has filed with EMEA for marketing authorization of their AAV product for a rare hereditary disorder, LPL deficiency; the company will soon file in Canada as well (the disorder is more prevalent in Quebec) (photo credit: Occhiovivo 2007)

2010 March 8 | Leave a comment | Tags:

BibTeX

@Manual{stream2010-70,
    title = {Ark, Troubled Waters, and Rainbows for Gene Transfer},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = mar,
    day = 8,
    url = {http://www.translationalethics.com/2010/03/08/ark-troubled-waters-and-rainbows-for-gene-transfer/}
}

MLA

Jonathan Kimmelman. "Ark, Troubled Waters, and Rainbows for Gene Transfer" Web blog post. STREAM research. 08 Mar 2010. Web. 05 Dec 2024. <http://www.translationalethics.com/2010/03/08/ark-troubled-waters-and-rainbows-for-gene-transfer/>

APA

Jonathan Kimmelman. (2010, Mar 08). Ark, Troubled Waters, and Rainbows for Gene Transfer [Web log post]. Retrieved from http://www.translationalethics.com/2010/03/08/ark-troubled-waters-and-rainbows-for-gene-transfer/

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Annus Mirabilis for Gene Transfer

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Time to review the year 2009 for cutting edge clinical research. For the field of gene transfer, it has been an annus mirabilis: a year that has seen very encouraging results in a wide variety of human clinical studies, as well as preclinical studies. Indeed, I regret that this blog has only been able to cover a few of the former, and very little of the latter. Here are a few highlights from clinical studies:


• in March 2009, Italian researchers reported major clinical improvement in eight of ten children participating in a gene transfer study involving ADA-SCID. [discussed here]

• in June 2009, researchers at Penn / Scheie Eye Institute reported very encouraging outcomes in three children with hereditary blindness, including evidence of visual recovery. [discussed here]

• in September 2009, researchers reported “marginal effectiveness” in preventing HIV infection for a gene transfer-based vaccine. These findings from this trial (the “RV144 trial”) were unexpected after abysmal trial results involving a related strategy (the STEP trials). These are the first encouraging results from any HIV vaccine study conducted to date. [described here and here].

• in November 2009, researchers at Paris-Necker reported very encouraging outcomes in two children with adreno leukodystrophy who received a vector derived from lentiviruses [discussed here]

The decade began with a series of very inauspicious clinical outcomes in gene transfer, and a sharp abatement in the volume of clinical testing. The decade ends with several highly encouraging results from well designed and executed clinical trials. (photo credit: Xavier Luque 2009)

2009 December 29 | Leave a comment | Tags:

BibTeX

@Manual{stream2009-75,
    title = {Annus Mirabilis for Gene Transfer},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = dec,
    day = 29,
    url = {http://www.translationalethics.com/2009/12/29/annus-mirabilis-for-gene-transfer/}
}

MLA

Jonathan Kimmelman. "Annus Mirabilis for Gene Transfer" Web blog post. STREAM research. 29 Dec 2009. Web. 05 Dec 2024. <http://www.translationalethics.com/2009/12/29/annus-mirabilis-for-gene-transfer/>

APA

Jonathan Kimmelman. (2009, Dec 29). Annus Mirabilis for Gene Transfer [Web log post]. Retrieved from http://www.translationalethics.com/2009/12/29/annus-mirabilis-for-gene-transfer/

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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)

2009 November 12 | Leave a comment | Tags:

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. 05 Dec 2024. <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/

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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)

| Leave a comment | Tags:

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. 05 Dec 2024. <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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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)

2009 June 23 | Leave a comment | Tags:

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. 05 Dec 2024. <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/

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Mice- Three Different Ones: Towards More Robust Preclinical Experiments

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One of the most exciting and intellectually compelling talks thus far at the American Society of Gene Therapy meeting was Pedro Lowenstein’s.  A preclinical researcher who works on gene transfer approaches to brain malignancies (among other things), Lowenstein asked the question: why do so many gene transfer interventions that look promising in the laboratory fail during clinical testing? His answer: preclinical studies lack “robustness.”


In short,  first-in-human trials are typically launched on the basis of a pivotal laboratory study showing statistically significant differences between treatment and control arms. In addition to decrying the “p-value” fetish- in which researchers, journal editors, and granting agencies view “statistical significance” as having magical qualities- Lowenstein also urged preclinical researchers to test the “nuances” and “robustness” of their systems before moving into human studies.

He provided numerous provocative examples where a single preclinical study showed very impressive, “significant” effects on treating cancer in mice. When the identical intervention was tried with seemingly small variations (e.g. different mouse strains used, different gene promotors tried, etc.), the “significant effects” vanished.  In short, Lowenstein’s answer to the question of why so many human trials fail to recapitulate major effects seen in laboratory studies is: we aren’t designing and reviewing preclinical studies properly. Anyone (is there one?) who has followed this blog knows: I completely agree. This is an ethical issue in scientific clothing. (photo credit: Rick Eh, 2008)

2009 May 29 | Leave a comment | Tags:

BibTeX

@Manual{stream2009-98,
    title = {Mice- Three Different Ones: Towards More Robust Preclinical Experiments},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = may,
    day = 29,
    url = {http://www.translationalethics.com/2009/05/29/mice-three-different-ones-towards-more-robust-preclinical-experiments/}
}

MLA

Jonathan Kimmelman. "Mice- Three Different Ones: Towards More Robust Preclinical Experiments" Web blog post. STREAM research. 29 May 2009. Web. 05 Dec 2024. <http://www.translationalethics.com/2009/05/29/mice-three-different-ones-towards-more-robust-preclinical-experiments/>

APA

Jonathan Kimmelman. (2009, May 29). Mice- Three Different Ones: Towards More Robust Preclinical Experiments [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/29/mice-three-different-ones-towards-more-robust-preclinical-experiments/

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Who says the British Press isn’t all yellow?  “Doctors have begun trials using gene therapy to treat patients for cystic fibrosis.”  So proclaims an April 19 story in the Guardian (“Cystic fibrosis to be treated by gene therapy technology”).  “Cystic fibrosis gene cure closer,” reads a Februrary 2009 BBC headline.

Details available
“‘We are not curing the condition,’ stressed scientist Dr. Deborah Gill. ‘We will merely be halting the erosion of patients’ lung function.'”(photo credit: Lisabuddka 2008)

2009 May 15 | Leave a comment | Tags:

BibTeX

@Manual{stream2009-101,
    title = {},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = may,
    day = 15,
    url = {http://www.translationalethics.com/2009/05/15/101/}
}

MLA

Jonathan Kimmelman. "" Web blog post. STREAM research. 15 May 2009. Web. 05 Dec 2024. <http://www.translationalethics.com/2009/05/15/101/>

APA

Jonathan Kimmelman. (2009, May 15). [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/15/101/

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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)

2009 May 12 | Leave a comment | Tags:

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. 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/

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