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11/12/2009 - 11:48am


(...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)

11/12/2009 - 10:51am

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)

11/08/2009 - 3:02pm

The attention and money thrown at the H1N1 virus seems to grow by the day, even if the numbers of H1N1 related deaths, relative to other causes of mortality (including plain old seasonal flu), are still very modest. People actually die from H1N1, so it is not nice to make light of it, and because it is contagious, the death toll will rise, though we don't know how high or for how long. Nevertheless, there is no way of getting around the impression that the world's media is drawn to the latest viral threat to the richer developed nations, where the knight in shining armour is played by multinational pharmaceutical companies, whose cutting-edge research thankfully produces the latest vaccine, while the media makes rapid and widespread vaccination seem like the only rational response, and governments and local health agencies stand to be criticized for not getting vaccines into bodies fast enough. The significance of the H1N1 virus as a threat to humanity? Only time will tell. But that a great deal of money is being made: that is already certain.

First, here in South Africa, some media sources managed to revive the discredited measles-autism link, i.e. that the measles vaccine causes autism in children. A little media ethics for journalists working on public health issues could go a long way, and hopefully these incidents will not cause setbacks for measles eradication in South Africa, similar to the problems with polio vaccination in Nigeria some years back. The recent decline in measles mortality in Africa is a success story, but only conserted and sustained efforts (including communication of accurate health information) will keep those numbers going down....

11/08/2009 - 3:02pm

The attention and money thrown at the H1N1 virus seems to grow by the day, even if the numbers of H1N1 related deaths, relative to other causes of mortality (including plain old seasonal flu), are still very modest. People actually die from H1N1, so it is not nice to make light of it, and because it is contagious, the death toll will rise, though we don't know how high or for how long. Nevertheless, there is no way of getting around the impression that the world's media is drawn to the latest viral threat to the richer developed nations, where the knight in shining armour is played by multinational pharmaceutical companies, whose cutting-edge research thankfully produces the latest vaccine, while the media makes rapid and widespread vaccination seem like the only rational response, and governments and local health agencies stand to be criticized for not getting vaccines into bodies fast enough. The significance of the H1N1 virus as a threat to humanity? Only time will tell. But that a great deal of money is being made: that is already certain.

First, here in South Africa, some media sources managed to revive the discredited measles-autism link, i.e. that the measles vaccine causes autism in children. A little media ethics for journalists working on public health issues could go a long way, and hopefully these incidents will not cause setbacks for measles eradication in South Africa, similar to the problems with polio vaccination in Nigeria some years back. The recent decline in measles mortality in Africa is a success story, but only conserted and sustained efforts (including communication of accurate health information) will keep those numbers going down....

11/04/2009 - 8:45pm

California's Institute for Regenerative Medicine just announced a series of large funding awards to fund translational research initiatives involving (mostly) stem cells. The projects funded are telling with respect to what was funded, and what they will attempt to achieve.
First, notwithstanding a press release containing the words "bringing stem cell therapies to the clinic," several projects are really dressed up gene transfer studies. Thus, one team will use gene transfer in hematopoietic stem cells for sickle cell anemia; another two will use gene transfer to stem cells for treating brain malignancies; another RNAi for HIV. All this is only further evidence that the field of stem cells is devouring gene transfer. Other projects are aimed more at getting "stem cells out of the clinic" by using small molecules or monoclonal antibodies to destroy stem cells causing malignancies.
Second is the sweeping ambition. As it stands today, only one clinical trial involving embryonic stem cell-derived tissues has been initiated. The projects funded under these awards are "explicitly expected to result in a filing with the FDA to begin a clinical trial." Given that these projects are funded for four years, CIRM seems to be banking on the prospect of at least a few of these initiating phase 1 trials within five years. Four of these proposals involve goals of implanting embryo-derived tissues, and two of these involve non-lethal conditions–macular degeneration and type I diabetes (technically, other awarded projects involve nonlethal, though extremely morbid conditions). Another involves implantation of embryo-derived tissues for Amyotrophic Lateral Sclerosis. It will be interesting to see how many of these meet their translational objectives, and how investigators will navigate the ethical, regulatory, and social complexity of initiating clinical testing. (photo credit: Michael Ransburg, 2008)

11/02/2009 - 4:27pm

There is always something a bit distasteful about comparing human tragedies, but it is also inevitable. The tsunami in 2004 was terrible, but was it as bad as the ongoing HIV/AIDS epidemic in Africa, which has taken millions of lives over the last decades? Darfur is bad, but has it really reached Rwandan genocidal proportions? We inevitably make these sorts of comparisons in order to get some sort of grip on what people ought to care about, and what nations ought to respond to with their finite resources. And we often lose our way.

11/02/2009 - 4:27pm

There is always something a bit distasteful about comparing human tragedies, but it is also inevitable. The tsunami in 2004 was terrible, but was it as bad as the ongoing HIV/AIDS epidemic in Africa, which has taken millions of lives over the last decades? Darfur is bad, but has it really reached Rwandan genocidal proportions? We inevitably make these sorts of comparisons in order to get some sort of grip on what people ought to care about, and what nations ought to respond to with their finite resources. And we often lose our way.

11/01/2009 - 10:26pm

Several blog posts ago, I wrote about the policy of accelerated approval (briefly, a mechanism whereby new drugs can be approved for sale by the FDA before definitive evidence of efficacy and safety are available). In that post, I reported on a recent paper where the authors claimed that, all things considered, accelerated approval enabled patients to get quicker access to life saving drugs without major adverse impacts on patient safety.
Last week, the Government Accounting Office issued a report on the subject that took a less favorable view of the program. Rules require that companies receiving accelerated approval for new drugs complete post-marketing studies confirming their efficacy. The GAO investigated the frequency with which companies fail to submit post-marketing trial data. They found that over a third of FDA-required post-marketing studies aimed at confirming efficacy had not yet been completed. Many of these studies might be incomplete because accelerated approval was only recently granted, and it can take as long as five years to complete requested studies. Disturbingly, however, the report found that a quarter of these studies had been incomplete for over five years; other studies have been completed but not yet reviewed by the agency. The figures are worse for other types of post-marketing studies requested by the agency.
The "poster boy" drug singled out in the GAO report is the hypertension drug Proamatine, which earned Shire Pharmaceuticals $257M since it was approved under accelerated approval 13 years ago. Apparently, the drug has not been subject to adequate confirmatory testing in all this time, though FDA has issued warning letters to the company over its promotion practices.
The report saves its criticism for the FDA, which it says has not reviewed sponsors' submissions in a timely manner, does not adequately monitor progress of post-marketing studies, and has neither specified conditions under which it would exercise its authority to withdraw drugs from market, nor has it ever exercised its authority to do so. But isn't some criticism also warranted for companies exploiting FDA's deficiencies? (photo credit: lindsay kay photography 2009)

10/28/2009 - 7:45pm

In a recent article in Science magazine, Constance Holden reports that European researchers are contemplating a revival of fetal tissue transplantation for the treatment of Parkinson’s disease. As the article recounts, fetal transplants were subjected to sham controlled studies in the late 1990s; none performed better than sham, and several caused disabling dyskinesias. So should fetal tissue transplantation be revived, and if so, how?
The challenges seem all the more formidable today. We now understand that Parkinson’s disease is not restricted to the dopaminergic neurons in the basal ganglia, but instead involves diffuse pathology. And yet, studies will not involve implantation of tissues throughout the brain. As Holden’s article points out, previous fetal transplant studies revealed that brain pathology spreads to implanted tissues, suggesting that permanent responses may be difficult to achieve.

The ethical issues seem just as daunting. Deep brain stimulation has greatly improved the management of Parkinson’s for patients who are no longer responding to dopamine replacement. And yet, those pursuing fetal tissue transplantation will likely advocate pursuing trials in younger patients with less advanced disease. As pointed out by a European team of researchers, "A significant effort of bioethical research and conceptual clarification is required in anticipation of the first protocols involving human subjects." And in a recently published article in Movement Disorders, several coauthors and I outline various ethical challenges presented by such studies. These include a high degree of uncertainty about the safety of interventions, and a baseline risk associated with delivery that approaches levels of risk encountered in phase 1 cancer trials (for studies that involve eight inoculations to the brain, risk of intracerebral brain hemorrhage leading to permanent neurological deficits is on the order of 2%).

Advocates of the new wave of studies insist we know much more about the properties of fetal tissues than we did in the 1990s; they further note that such studies will provide a basis for later studies involving induced pluripotent stem cells and other tissues. Perhaps, but given the remaining uncertainties and promise of DBS, it’s hard to imagine how fetal graft experiments could credibly establish a claim of clinical equipoise with deep brain stimulation. For these reasons, a more prudent ethical course—if fetal transplant studies for Parkinson's are to be done at all—would be to pursue safety and feasibility studies in patients who are no longer responsive to standard care. Only once parameters are optimized and mechanisms well understood should clinicians consider studies in patients who are earlier in the disease process. (photo credit: Ethan Hein 2008)

10/26/2009 - 4:54pm

Followers of this blog may recall my continuing concern with the way informed consent is obtained in phase 1 trials involving patient-volunteers (typically, these patients have exhausted standard care options and enter phase 1 trials as a final shot at managing their disease). Language used by investigators in these studies is often suggestive of therapeutic benefit, even though meta-analyses of phase 1 studies show that chances of major clinical benefit in phase 1 studies are exceedingly low. In previous posts, I described my own experience with an ethics review committee that actually defended giving patients vague and almost meaningless information about the therapeutic benefits of phase 1 trial participation. Meantime, evidence from surveys indicate that phase 1 cancer patient-volunteers tend to overestimate the probability of therapeutic benefit.
In the July-August 2009 edition of the ethics journal IRB, Shlomo Koyfman and co-authors at NIH offer up a "Consent Form Template for Phase I Oncology Trials." Their recommendations are comprehensive and excellent. Among the items they recommend are:
• use of more therapeutically neutral language, like "research agent" instead of "therapy"
• disclosure of dose escalation design; in particular, the authors recommend that patients be informed about risks and benefits relative to the cohort they are entering.
• a statement (where appropriate) that patient-volunteers will not have the option of adjusting their dose assignment in the study
• a statement that "the chances that this agent will... allow you to live longer [is] very low."
One can quibble with various particulars (I think, for example, discussion of subtherapeutic dosing should be more explicit). But on the whole, these recommendations provide an excellent standard– along with NIH Guidance on Informed Consent for Gene Transfer Research– against which typical phase 1 cancer study consent forms should be measured. (photo credit: banlon1964)