Transplanting Autoimmune Research

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What’s the difference between testing a typical small molecule drug, and testing a novel cell therapy strategy? And where might the latter raise ethical challenges that the former doesn’t? These questions are extensively discussed in my book, and given human drama in a recent story by Jennifer Couzin-Frankel in the Feb 12, 2010 issue of Science (“Replacing an Immune System Gone Haywire“).


Couzin-Frankel describes the numerous difficulties that researchers have faced in attempting to validate autologous bone marrow transplantation for the treatment of (often nonlethal but highly debilitating) autoimmune disorders like type 1 diabetes, Crohn’s disease, and multiple sclerosis. The idea of this procedure is to “reset” the immune system by purging patients of their bone marrow cells, and then returning healthy bone marrow to them. The approach has shown some promise for certain autoimmune disorders. However, response is highly variable and unpredictable, and validating and applying bone marrow transplantation for autoimmune disorders is beset by numerous ethical and logistical difficulties.

A major one is the risk-benefit balance: bone marrow transplantation requires exposing patients to the dangers of the transplantation procedure (6.6% mortality in one report of lupus patients). And yet, the procedures appear to work better in patients whose disease is not yet advanced. Testing the procedure therefore requires recruiting more or less healthy, at risk patients (sometimes children) into studies that expose them to serious risk of mortality. Clinicians understandably balk at referring their patients to such studies, making recruitment very difficult.

A second challenge is funding: many of these approaches involve using the patient’s own bone marrow cells. There is nothing to patent– and hence, little commercial interest in bone marrow transplantation for autoimmune disorders. This deprives this promising line of research needed resources.

And all this creates the perfect storm for a series of ethical challenges not directly addressed in this article (but covered in my book and articles): the siting of such studies in low and middle-income settings. Prohibitive costs, plus extreme difficulty recruiting patients who are otherwise eligible for somewhat effective and extremely expensive monoclonal antibody therapies, makes the siting of such trials in economically disadvantaged settings very attractive. This gives rise to what I have elsewhere called “expedient” justification for recruitment. Not surprisingly, then, one of the first trials of the procedure was performed in Brazil, and the article closes by mentioning that ongoing trials involving high-income country researchers are recruiting from São Paulo, Prague, China, and Argentina. This is good news if people in those settings have a reasonable prospect of having widespread and affordable access to bone marrow transplantation once it becomes validated. But it is troubling indeed if people in these countries will be bearing considerable burdens for the sake of knowledge benefits that will primarily (or most expeditiously) accrue to patients in high-income settings. (photo credit: Wellcome Images, Compact Bone, 2009)

BibTeX

@Manual{stream2010-72,
    title = {Transplanting Autoimmune Research},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = feb,
    day = 26,
    url = {http://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/}
}

MLA

Jonathan Kimmelman. "Transplanting Autoimmune Research" Web blog post. STREAM research. 26 Feb 2010. Web. 17 Oct 2019. <http://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/>

APA

Jonathan Kimmelman. (2010, Feb 26). Transplanting Autoimmune Research [Web log post]. Retrieved from http://www.translationalethics.com/2010/02/26/transplanting-autoimmune-research/


Remembrance of Things Past: Fetal Tissue Transplantation and Parkinson’s Disease

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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)

BibTeX

@Manual{stream2009-82,
    title = {Remembrance of Things Past: Fetal Tissue Transplantation and Parkinson’s Disease},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = oct,
    day = 29,
    url = {http://www.translationalethics.com/2009/10/29/remembrance-of-things-past-fetal-tissue-transplantation-and-parkinsons-disease/}
}

MLA

Jonathan Kimmelman. "Remembrance of Things Past: Fetal Tissue Transplantation and Parkinson’s Disease" Web blog post. STREAM research. 29 Oct 2009. Web. 17 Oct 2019. <http://www.translationalethics.com/2009/10/29/remembrance-of-things-past-fetal-tissue-transplantation-and-parkinsons-disease/>

APA

Jonathan Kimmelman. (2009, Oct 29). Remembrance of Things Past: Fetal Tissue Transplantation and Parkinson’s Disease [Web log post]. Retrieved from http://www.translationalethics.com/2009/10/29/remembrance-of-things-past-fetal-tissue-transplantation-and-parkinsons-disease/


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