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Answer: Marrow Stem Cell Transplantation in Fibrodysplasia Ossificans Progressiva

2001; Lippincott Williams & Wilkins; Volume: 392; Linguagem: Inglês

10.1097/00003086-200111000-00060

1528-1132

Stephen G. Emerson, Frederick S. Kaplan,

Bone Tumor Diagnosis and Treatments

Fibrodysplasia ossificans progressiva is the most extensive disorder of heterotopic osteogenesis in humans and results in postnatal formation of an ectopic skeleton. Progressive episodes of heterotopic ossification begin in childhood and lead to ankylosis of all major joints of the axial and appendicular skeleton, rendering movement impossible. Disease progression is heralded by painful episodic flareups that occur spontaneously or after minor soft tissue trauma and are characterized by warm, tender, and highly vascular preosseous fibroproliferative lesions that develop through an endochondral process to form mature heterotopic bone. Although the rate of disease progression is variable, most patients are confined to a wheelchair by their early twenties and require lifelong assistance in performing activities of daily living. Surgical trauma associated with resection of heterotopic bone leads to exacerbation of local ossification. Currently, there is no effective prevention of treatment. Accordingly, medical intervention currently is supportive. 10 The ultimate goal of fibrodysplasia ossificans progressiva research is the development of treatments that will prevent, halt, or even reverse the progression of the condition. To best achieve that goal, it is imperative to determine the molecular and genetic cause of the disease. But, it also is necessary to integrate those molecular and genetic details into the developmental, metabolic, and physiologic pathways through which the putative damaged gene causes progressive and disabling heterotopic ossification. 8,10,18 Recent advances in basic and clinical research suggest that stem cells may lie at the heart of a cure for fibrodysplasia ossificans progressiva. Hematopoietic cells have been found in biopsies of lesions, 8 and stem cells have been found to give rise to multiple mesenchymal tissues, including muscle and bone. 2,4,9,16,20 Given these new insights, it is rational to ask whether patients with fibrodysplasia ossificans progressive should be treated by replacement of their hematopoietic stem cell pool, via bone marrow, peripheral blood, or umbilical cord blood stem cell transplantation. To answer this question, it is essential to realize how stem cell transplantation might cure fibrodysplasia ossificans progressiva, how it might fail, and the clinical risks that patients would necessarily undergo to obtain the chance for cure via current stem cell transplantation techniques. How Might Stem Cell Transplantation Successfully Treat or Cure Fibrodysplasia Ossificans Progressiva? In light of the data indicating that Epstein-Barr virus transformed lymphoblastoid cell lines from patients with fibrodysplasia ossificans progressiva express abnormally high levels of messenger ribonucleic acid and protein for bone morphogenetic protein-4, it hypothetically is possible that an abnormal hematopoietic cell, perhaps lymphoid or myeloid, could trigger the pathophysiology of fibrodysplasia ossificans progressiva. 1,7,18 Although there is no evidence that the leukocytes secrete bone matrix proteins, cells such as fibroblasts, myoblasts, pericytes, or other mesenchymal cells could lay down the bony exoskeleton in response to abnormal osteoinductive signals from leukocytes. 2–4,16 If fibrodysplasia ossificans progressiva is triggered by abnormal osteogenic proteins produced by leukocytes, then complete replacement of the hematopoietic compartment by stem cell transplantation would eliminate permanently the pathogenetic fibrodysplasia ossificans progressiva cells. Although the genetic abnormality still would be present in the patient, the cells capable of expressing the abnormality would be removed. Moreover, even if a small percentage of abnormal hematopoietic cells remained immediately after the transplant, they would be eliminated over several months by the new immune system arising from the transplanted cells. Therefore, the fibrodysplasia ossificans progressiva essentially would be cured by the stem cell transplantation procedure. Even if abnormal blood cells do not trigger bony deposition in patients with fibrodysplasia ossificans progressiva, stem cell transplantation still could cure the disease. We now know that cells found within the stem cell compartment within the bone marrow and blood are capable of giving rise to endothelial cells, muscle cells, cartilage, and even neurons. 2,16,20 Moreover, transplanted stem cells have been shown to contribute cardiac myocytes to repairing myocardial infarcts, and to partially correct neurologic defects after cerebral ischemia. 16 Therefore, it is conceivable that stem cell transplantation procedures could lead to amelioration or cure fibrodysplasia ossificans progressiva even if the pathogenetic cells were muscle, endothelial, or other connective tissue. Over months to years, turnover of patient tissues by new cells derived from the transplanted stem cells gradually would reduce the burden of diseased mesenchyme. Why Might Stem Cell Transplantation Fail to Successfully Treat or Cure Fibrodysplasia Ossificans Progressiva? If Fibrodysplasia Ossificans Progressiva is Caused by the Response of an Abnormal Soft Tissue Cell to Trauma and Not to an Abnormal Inflammatory (blood) Cell At this time, although studies show that stem cells can generate soft tissue cells from many lineages, this seems to be a very low efficiency process. In vitro, fewer than one bone marrow cell in five million has the potential to generate mesenchymal cells, and the number of cells produced from each mesenchymal stem cell is finite. After current stem cell transplantation protocols, only very small numbers, probably less than 0.1% of total mesenchymal cells of any lineage, can be found to be donor-derived even months to years after stem cell transplantation. Therefore, without new advances in stem cell transplantation techniques, this process is not likely to be efficient enough to replace most of the abnormally responding myoblasts, fibroblasts, endothelial cells, pericytes, or other mesenchymal cells. 13,16,20 If Fibrodysplasia Ossificans Progressiva is Caused by Abnormal Inflammatory Cells Allogeneic bone marrow transplantation most often replaces all of the hematopoietic cells so this should cure the disease. However, turnover is not instantaneous, particularly for monocytes, macrophages, T cells, and B cells. Immediately after traditional allogeneic transplantation, there is a tremendous inflammatory response to the chemotherapy or radiotherapy, or both, which could cause the remaining abnormal hematopoietic cells to activate and trigger promiscuous and catastrophic heterotopic ossification. Even during the following 6 to 12 months, residual host monocytes, macrophages, and lymphoid cells could trigger heterotopic bone. Although the frequency and severity of such episodes would in theory decline with time, the patient could die of complications before a cure could be effective. If the Patients Are Too Medically Compromised to Withstand the Transplant and Its Ensuing Complications Whatever the cellular genesis of fibrodysplasia ossificans progressiva, to cure the disease by stem cell transplantation requires that the patients survive the extremely dangerous stem cell transplantation. Allogeneic transplantation is accompanied by a prolonged period of immunodeficiency, in which the patients are at heightened risk for viral, bacterial, and fungal infections. Patients with fibrodysplasia ossificans progressiva have severe restrictive chest wall disease with a dramatically increased risk of pulmonary compromise and pneumonia even during childhood. 11 In addition, the engrafting immune system often recognizes the patient’s tissues as foreign and attempts to reject them (graft-versus-host disease). Overall, the mortality of allogeneic bone marrow transplantation as currently performed, in any scenario, always is greater than 10% to 15% and can be 50% or greater in some settings. If Fibrodysplasia Ossificans Progressiva Is Caused by Some Unforeseen Cell and Mechanism Without knowing the cellular cause of fibrodysplasia ossificans progressiva, we still could be missing the true therapeutic target of the underlying pathophysiologic process. 10 We could perform a nontoxic, successful allogeneic stem cell transplantation for a patient, and still not cure the disease. This creates a serious conundrum. Stem cell transplantation is theoretically a very attractive approach to cure fibrodysplasia ossificans progressiva, but it could be dangerous, without any guarantee of cure, or even benefit. To compound the problem, if a patient was not cured, or died during a transplant, we might not know why the treatment had failed. Without an abnormal gene or cell to follow, the clinician would be entering a truly blinded trial. Given that most patients with fibrodysplasia ossificans progressiva are not in a truly life-threatening clinical condition, and that severely affected patients would be at the highest risk for transplant morbidity and mortality, stem cell transportation at present would be extremely risky. What Would Favor the Therapeutic Index in the Direction of Stem Cell Transplantation for Fibrodysplasia Ossificans Progressiva? Fundamentally, the therapeutic index for bone marrow stem cell transplantation in patients with fibrodysplasia ossificans progressiva must be improved by decreasing the risk of the transplant procedure or improving the likelihood of success or both. Several approaches to decreasing the toxicity of stem cell transplantation are ongoing. These include: (1) nonmyeloablative stem cell transplantation, which may decrease transplant morbidity by decreasing inflammation and encouraging gradual, progressive chimerism 12,15; (2) artificial thymic organoids, which might be used to prevent posttransplant immunodeficiency and graft-versus-host disease 17; and (3) novel pharmaceuticals to prevent graft-versus-host disease, such as antigranzyme and antiFas reagents, and antidendritic cell antibodies. 5,6,14,19 Increasing the likelihood of therapeutic efficacy, however, requires the identification of the cellular trigger of fibrodysplasia ossificans progressiva, and ideally the genetic defect. This will allow preclinical investigations, perhaps in a xenogeneic stem cell transplantation model where stem cell enriched peripheral blood cells from patients with fibrodysplasia ossificans progressiva are transplanted into nonobese diabetic and severe combined immunodeficient mice, so that treatment modeling for fibrodysplasia ossificans progressiva can be investigated before the first clinical transplant is done in humans. Our recent understanding of the biology of stem cells has expanded to the point that nearly all tissues can be seen as repopulating from a small pool of tissue-specific stem cells, which may originate from a rare but ever present pool of pluripotent stem cells found in the bone marrow and in the circulation. Given this knowledge, it is extremely likely that stem cells will find a pivotal role in the treatment of diseases that arise from within one diseased cell or tissue. Our challenge as clinicians and scientists is to advance the field of stem cell biology, and our understanding of specific diseases such as fibrodysplasia ossificans progressiva, so that decisive therapies can be offered to patients in the context of clinical trials that maximize potential patient benefit while minimizing the chances to do them harm. For those of us working in critical aspects of stem cell biology, and for those of us caring for patients with fibrodysplasia ossificans progressiva, the hour has not yet arrived, and the clock still is ticking.