Predictably, the big presidential symposium at ASGCT reserved a slot for Jean Bennett, who led one of the three teams that have tested a gene transfer strategy for a rare genetic form of blindness, Leber’s Congenital Amaurosis (LCA). Unpredictably, however, Bennett trotted out one of her “treated” patients, Cory Haas, along with his two parents, who sat up on the podium as Bennett went through her 45 minute presentation, which was titled “An Aye for Gene Therapy.”
First, let me say that Bennett’s results- as well as those of the other teams- continue to be very encouraging. In adults whose retinal tissues have degenerated, the approach has not restored vision, but it has also not raised any major safety concerns (apart from a surgical complication in one patient). In younger patients, the approach has shown safety with restoration of vision, and Bennett this time presented various functional data, along with neuroimaging data consistent with restoration of vision. And nothing that follows detracts from all the credit she and her team deserve for their smarts, scientific rigor, perseverance, and clinical accomplishments. Second, the family has agreed to go public, and this was not their first time on display. No doubt, they feel that putting themselves on display like his helps bring visibility to this important research. As well, they have their own battles to fight: only one eye has been corrected, and perhaps they feel that going public like this may help nudge regulatory authorities to clear the investigators to apply gene transfer to the second eye.
Nevertheless, I found Bennett’s exhibition of her subject, and his parents, a case of poor judgment. And judging from one or two conversations with others in attendance, I was not alone. In my book, I warn against the perils of putting patients on display. It performs a rhetorical function that tends to neutralize critical thinking and indulge sentimentality. I found it particularly problematic that this would occur at a major scientific address: if there were skeptical questions to be asked (as there typically are at scientific meetings), who would dare ask them in front of a child and his parents? At any rate, Bennett used a short question and answer period following her talk by asking Corey and his parents a series of Diane Sawyer-like questions: “are you glad you joined the study?” “what was the most difficult part?” “do you have any questions?” She then elicited a round of applause “for the patients” from the >500 assembled attendees. Was the Q and A scripted? Was this a kind of victory lap for Bennett? Who knows.
Spectacular research, to be sure. But it makes for spectacle science as well. (photo credit: strangejourney 2009)
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Jonathan Kimmelman. "ASGCT, continued: Eyes on Stage" Web blog post. STREAM research. 25 May 2010. Web. 29 Apr 2024. <http://www.translationalethics.com/2010/05/25/asgct-continued-eyes-on-stage/>
APA
Jonathan Kimmelman. (2010, May 25). ASGCT, continued: Eyes on Stage [Web log post]. Retrieved from http://www.translationalethics.com/2010/05/25/asgct-continued-eyes-on-stage/
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)
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MLA
Jonathan Kimmelman. "Ark, Troubled Waters, and Rainbows for Gene Transfer" Web blog post. STREAM research. 08 Mar 2010. Web. 29 Apr 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/
Last year’s “big ticket” item at ASGT was results from the first three patients in two gene transfer trials testing nearly identical products against a rare form of congenital blindness, Leber’s Congenital Amaurosis (LCA). I previously blogged (here and here and here and elsewhere) on the controversial decision to move the intervention into children, given the novelty of the intervention, that the trial is primarily a safety study, and that blindness is not a fatal condition.
Today, Jean Bennett of University of Pennsylvania presented an update on the first three patients (previously reported in New England Journal of Medicine) plus results on the next three patients. Here’s a synopsis. The first three patients continue to show dramatic improvement in objective measures like pupillometry (that is, their pupils are responding to flashes of light in a way that does not normally occur in patients with this form of blindness), and they show signs of improved vision.
The next three patients were children eight years or a bit older. Bennett showed dramatic footage of a child unable to find his way through a maze when using the uncorrected eye, and navigating a maze with relative ease with the corrected eye. She also showed data indicating retinal function in regions of the eye receiving vector. Improvements in vision were greater with the children than in the previous cohort- which she chalked up to the fact that retinal tissue was not as degenerated in younger patient-volunteers. The team did not observe any gene transfer-related adverse events.
The other two LCA trials were conspicuously missing from the meeting. Rumor has it that the Penn team has been far more successful recruiting patients with this rare disorder. Bennett flashed a slide at the beginning of her presentation showing that patients had been accrued from several continents- North America, Africa, Europe, and elsewhere. Patients in the second cohort, according to Bennett, are begging to have their second eye dosed. (photo credit: Ferran 2009).
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Jonathan Kimmelman. "The Vision Thing: Update on LCA" Web blog post. STREAM research. 30 May 2009. Web. 29 Apr 2024. <http://www.translationalethics.com/2009/05/30/the-vision-thing-update-on-lca/>
APA
Jonathan Kimmelman. (2009, May 30). The Vision Thing: Update on LCA [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/30/the-vision-thing-update-on-lca/
This year’s annual meeting of the American Society of Gene Therapy is in San Diego. I’ve been to several interesting talks thus far, and plan to post entries on a few. For now, here’s an overview of some major (or some not so major) clinical developments in gene transfer that are being reported at this meeting.
1- Last year, I predicted that the first gene transfer applications were nearing licensure. Not so fast. Because of concurrent sessions, I was unable to attend the entire talk given by Robert Shaw of the British biotech company Ark Therapeutics. Ark has developed a gene transfer approach, Cerepro, that uses adenovirus to treat malignant glioma (which is one of the most aggressive types of cancer). Ark recently applied to the European drug regulatory authority, EMEA, for registration of Cerepro. Why not FDA? Dunno (though the speaker stated that the review standards are more or less the same). The data behind the product are less than earth shaking. According to information available over the web [proviso- these data are from August 2008], the pivotal phase 3 study of Cerepro showed only a 42-day increase in survival for patients in the active drug arm. And the product caused “increases” in hemiparesis, aphasia, and fever.
2- Another somewhat discouraging indication of the challenges in reaching licensure for gene transfer products was a session titled “late stage industry clinical trials.” To me, late stage means phase 3. But three talks centered on phase 1/2 studies, and none presented phase 3 results. The first talk was given by Ceregene on their Parkinson’s disease product Cerepro. The product did not show any significant advantage over sham for their primary endpoint.
3- Last year, the “buzz” at ASGT was the preliminary results from three studies testing AAV vectors for a form of congenital blindness, LCA. I also discussed the somewhat ethically controversial decision to move this study into children. I will look forward to attending Jean Bennett’s talk on Friday; her abstract reports that her LCA study has enrolled “9 children and young adults” ranging from age 8 to 26 years. The abstract claims improvement in “subjective and objective” measures of vision. To be continued… (photo credit: slack12, 2008)
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Jonathan Kimmelman. "ASGT in San Diego" Web blog post. STREAM research. 28 May 2009. Web. 29 Apr 2024. <http://www.translationalethics.com/2009/05/28/asgt-in-san-diego/>
APA
Jonathan Kimmelman. (2009, May 28). ASGT in San Diego [Web log post]. Retrieved from http://www.translationalethics.com/2009/05/28/asgt-in-san-diego/
(…continued from previous posts). The promising results, and the surge of expectation they generated, will be used by the investigators and many advocates for the blind to defend pursuing the remainder of the study in children. After all, children stand a better chance of benefiting, because their retinas have not yet degenerated.
Traditionally, bioethicists have frowned on pursuing studies in children that could otherwise be done in adults, because children are unable to provide valid consent. Given that the primary objective of the study is safety, and that a sample size of 3 (or, combining the two studies, 6) and a follow-up of less than a year is minimally meaningful in terms of projecting safety, many bioethicists would question the prudence of continuing the study in pediatric populations.
The third volunteer in the Moorfield study was not an adult. A report in Science magazine (2 May 2008) indicates that the Philadelphia team will test the agent next in an eight-year-old.
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Jonathan Kimmelman. "Kid Time for LCA gene transfer?" Web blog post. STREAM research. 15 May 2008. Web. 29 Apr 2024. <http://www.translationalethics.com/2008/05/15/kid-time-for-lca-gene-transfer/>
APA
Jonathan Kimmelman. (2008, May 15). Kid Time for LCA gene transfer? [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/15/kid-time-for-lca-gene-transfer/
(…continued from previous post) Whatever the ambiguity and severe limitations in terms of sample size and interpretability, the NEJM studies have unleashed a torrent of expectation. Accoding to the U.K. Guardian, “an 18-year-old man… has amazed doctors by navigating a maze…” and the technique “represented a ‘huge advance.'”
The Washington Post’s Rick Weiss was harshly critical of Targeted Genetics when a volunteer died in a study involving AAV vectors and arthritis. Those who view Weiss as sour on gene transfer should consider his enthusiastic coverage of the LCA results. The lede states unequivocally that three volunteers “regained modest amounts of vision,” and describes the results as “something short of miraculous.”
In Canada, the Globe and Mail’s Hayley Mick reports on a Canadian undergoing a similar procedure in Florida (their results are unpublished). “Within weeks, the patients who took part [in the Penn and U.K.] trials reported varying degrees of vision improvement.”
Per usual, all three present a human drama narrative– which is certain to amplify expectations further– naming (and in some cases, photographing) two volunteers: Dale Turner and Steven Howarth. (to be continued…photo credit: GiantsFanatic 2007)
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Jonathan Kimmelman. "Imprinting Expectation" Web blog post. STREAM research. 06 May 2008. Web. 29 Apr 2024. <http://www.translationalethics.com/2008/05/06/imprinting-expectation/>
APA
Jonathan Kimmelman. (2008, May 06). Imprinting Expectation [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/06/imprinting-expectation/
…continued from previous post: So did the researchers make the blind see? Any suggestion that vision has been restored is premature. The authors of both reports acknowledge that measures of vision are subjective and visual improvements might reflect a placebo effect. What can be said– at least of the U.S. study– is that the pupil reflex is behaving as if the eye (and brain) are responding to visual stimuli better than before the experiment.
Many will view these two studies as confirmation of the promise of gene transfer– as evidence that gene transfer, in the words of one leader in the field, “has turned a corner.” Though I understand the sentiment and view these results as encouraging, I also worry about the way these modest findings are being amplified into a signal event. (to be continued…photo credit: daniel y go, 2008)
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Jonathan Kimmelman. "Seeing Light?" Web blog post. STREAM research. 02 May 2008. Web. 29 Apr 2024. <http://www.translationalethics.com/2008/05/02/seeing-light/>
APA
Jonathan Kimmelman. (2008, May 02). Seeing Light? [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/02/seeing-light/
...continued from previous post: The preclinical studies supporting these human trials are about as good as it ever gets in translational research: numerous large animals (dogs) were treated effectively, and their vision in treated eyes seems to have been restored out to as much as eight years.
The NEJM papers report delivering nearly identical vectors to one eye of volunteers with Leber’s Congenital Amaurosis type 2 (LCA2). The U.K. group did not observe any clinically “significant improvement in visual acuity,” though one of the three volunteers showed some improved retinal function. The U.S. group (based at the University of Pennsylvania) shows significant improvement using an ostensibly objective measure– the pupillary light reflex. The authors also claim all three volunteers had improved visual acuity.
Importantly, neither group reported any adverse events attributable to the gene transfer product. No immune response to the transgene was detected in sera. Immune response to vector was detected in only one instance– and only transiently. Importantly, no vector was detected outside the eye. Thus, the vector does not appear to present any really big, extremely common, and almost immediate safety concerns. All good. (to be continued…photo credit: lu lacerda 2007)
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Jonathan Kimmelman. "Safety First: Two Gene Transfer Studies Against Blindness" Web blog post. STREAM research. 01 May 2008. Web. 29 Apr 2024. <http://www.translationalethics.com/2008/05/01/safety-first-two-gene-transfer-studies-against-blindness/>
APA
Jonathan Kimmelman. (2008, May 01). Safety First: Two Gene Transfer Studies Against Blindness [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/01/safety-first-two-gene-transfer-studies-against-blindness/
This week, the New England Journal of Medicine published two preliminary trial reports using gene transfer against a rare form of congenital blindness– Leber’s Congenital Amaurosis type 2. Since Jean Bennett and coworkers at the University of Pennsylvania reported in 2001 successfully correcting visual deficiencies in dogs afflicted with a nearly identical genetic condition, the field of gene transfer has been atwitter with anticipation of these results.
In the next few posts, I will comment on the studies, the science, the ethics, and the reporting of the LCA studies. (photo credit: chrisphoto, optomap retina scan, 2005)
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Jonathan Kimmelman. "Envisioning Gene Transfer: Report on Congenital Blindness Studies" Web blog post. STREAM research. 01 May 2008. Web. 29 Apr 2024. <http://www.translationalethics.com/2008/05/01/envisioning-gene-transfer-report-on-congenital-blindness-studies/>
APA
Jonathan Kimmelman. (2008, May 01). Envisioning Gene Transfer: Report on Congenital Blindness Studies [Web log post]. Retrieved from http://www.translationalethics.com/2008/05/01/envisioning-gene-transfer-report-on-congenital-blindness-studies/
Predictably, the big presidential symposium at ASGCT reserved a slot for Jean Bennett, who led one of the three teams that have tested a gene transfer strategy for a rare genetic form of blindness, Leber’s Congenital Amaurosis (LCA). Unpredictably, however, Bennett trotted out one of her “treated” patients, Cory Haas, along with his two parents, who sat up on the podium as Bennett went through her 45 minute presentation, which was titled “An Aye for Gene Therapy.”
