editorial to previous post..
Early Use of Drastic Therapy
Kenneth I. Weinberg, M.D.
Krabbe's disease, or globoid-cell leukodystrophy, is an inborn error of lipid metabolism first described in 1916 in two children with spasticity who died in infancy and were found to have "diffuse sclerosis" of the brain.1 Prominent features of the brain in affected children were decreased white-matter mass with relatively normal gray matter, generalized demyelination, and clusters of globoid cells in the white matter. Subsequent histopathological analyses have demonstrated that the changes in the white matter are due to the death of the myelin-forming oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system, whereas the characteristic globoid cells are reactive mononuclear phagocytes.2 The globoid cells found in the brains of children with Krabbe's disease contain abnormally high levels of galactocerebroside (also known as galactosylceramide). The primary genetic defect is loss-of-function mutations in the gene encoding the lysosomal enzyme galactocerebrosidase (galactosylceramide -galactosidase), which catalyzes the cleavage of galactocerebroside to galactose and ceramide.2
For some lysosomal storage diseases, replacement of the deficient enzyme (e.g., enzyme replacement with recombinant glucocerebrosidase in patients with Gaucher's disease) may correct the biochemical abnormality and improve clinical status.3 However, the success of enzyme replacement for metabolic diseases depends on the stability and tissue distribution of the enzyme in vivo and the ability of the enzyme either to enter cells or to metabolize extracellular substrate. At present, enzyme-replacement therapy for Krabbe's disease is not available.
Another potential approach to the treatment of storage diseases is hematopoietic stem-cell transplantation. The scientific premise for such studies is that any genetic disease of lymphohematopoiesis (including primary lymphocyte defects, such as severe combined immunodeficiency and the Wiskott–Aldrich syndrome, and hemoglobinopathies, such as -thalassemia) can be cured by the replacement of host hematopoietic stem cells that contain deleterious mutations with hematopoietic stem cells from a healthy donor.4 Treatment generally involves the administration of busulfan to ablate the defective hematopoietic stem cells, thereby creating a selective advantage for the donor-derived hematopoietic stem cells, and the administration of cyclophosphamide and antithymocyte globulin to eliminate the lymphocytes that might mediate immunologic rejection of the allogeneic stem cells. For metabolic diseases, the ultimate goal is to permit the continued production of normal mononuclear phagocytes. Diseases of tissue macrophages that can be treated in this way include lysosomal storage diseases such as Gaucher's disease and infantile osteopetrosis, a disease of osteoclasts.
For diseases of the central nervous system, hematopoietic stem-cell transplantation can result in the continuous production of normal microglia, which have been shown to be derived from hematopoietic stem cells.5,6,7 Microglia of donor origin may be capable of producing normal amounts of a missing enzyme, thus detoxifying the brain by metabolizing the deleterious substrate. However, a difficulty with the application of hematopoietic stem-cell transplantation to metabolic diseases is the low rate of turnover of macrophages. Normal macrophages may not replace the patient's abnormal cells for three to six months after transplantation, during which time irreversible damage may occur.8,9
In this issue of the Journal, Escolar et al. describe outcomes of hematopoietic stem-cell transplantation in infants with Krabbe's disease.10 Previous studies in murine models and in patients with late-onset Krabbe's disease had suggested some improvement in the course of the disease after hematopoietic stem-cell transplantation.11,12 The study by Escolar et al. involved transplantation with cord-blood cells from unrelated donors. Because these cells are banked as cryopreserved units, transplantation can be performed much more expeditiously than transplantation involving the collection of allogeneic peripheral or bone marrow stem cells from unrelated adult donors.
The babies in the study received busulfan, cyclophosphamide, and antithymocyte globulin. Eleven patients were asymptomatic newborns in whom Krabbe's disease had been diagnosed either in utero or immediately after birth because of a positive family history. Fourteen patients were older infants in whom the diagnosis had been made after manifestations of Krabbe's disease had developed. At 4 to 66 months of follow-up, there was 100 percent survival and donor hematopoietic stem-cell engraftment in the asymptomatic group but only 43 percent survival in the symptomatic group. Similarly, survival after hematopoietic stem-cell transplantation for other genetic diseases (such as severe combined immunodeficiency, the Wiskott–Aldrich syndrome, or thalassemia) is decreased by older age, end-organ dysfunction, or decreased performance scores.4
In addition to their improved survival, the infants who were asymptomatic at the time of transplantation had ongoing cognitive development after transplantation, whereas the symptomatic patients continued to have rapid disease progression despite donor stem-cell engraftment. Motor abnormalities continue to appear in the initially asymptomatic group but have not been as severe as in untreated patients. The difference in outcome between the two groups indicates that there is a critical time window for the correction of Krabbe's disease.
The window of opportunity for therapy is consistent with a novel explanation of the pathophysiology of Krabbe's disease, which has been called the "psychosine hypothesis."2,13 This hypothesis holds that the massive dropout of oligodendrocytes and the relative paucity of galactocerebroside storage material in Krabbe's disease could be explained by the toxic effects of galactosylsphingosine, or psychosine, a less abundant substrate for galactosylceramidase.14 Unlike other sphingolipids, psychosine is capable of inducing apoptosis, resulting in irreversible damage to oligodendrocytes in patients who undergo transplantation at an older age. The psychosine hypothesis also may explain the observed motor defects after early transplantation. The long nerve tracts needed for motor function may be more sensitive to a small degree of destruction of myelin than is the central nervous system white matter needed for continued cognitive development. Alternatively, there may be fewer donor-derived cells in motor tracts that are capable of metabolizing psychosine; for example, donor-derived endoneurial macrophages in the peripheral nervous system may be less common than the microglia in the central nervous system.
A possible strategy to overcome the problem of delayed production of donor-derived microglia might be to combine hematopoietic stem-cell transplantation with biochemical therapies, which would permit preservation of myelin-forming cells while donor microglia are still being formed. In this regard, L-cycloserine, which inhibits the production of psychosine, was reported to slow the progression of disease in a "twitcher" mouse model of late-onset Krabbe's disease.15 Data are needed to determine whether such strategies might further improve outcomes of transplantation in infants with early-onset Krabbe's disease.
The article by Escolar et al. also raises broader questions about how we may best confront serious pediatric diseases. Hematopoietic stem-cell transplantation is still considered by most practitioners to be a high-risk therapy of last resort. The tendency has been to test risky therapies first in adults or older children who can make informed decisions about participating and in patients who are already ill from their disease, for whom the risks of therapy seem less extreme. For example, hematopoietic stem-cell transplantation for Krabbe's disease was previously performed in symptomatic older children with late-onset disease.12 If the study of Escolar et al. had been restricted to the symptomatic infants, the investigators would have concluded that hematopoietic stem-cell transplantation was ineffective.
The study by Escolar et al. makes it clear that in some circumstances, the subjects who derive the greatest benefit may be those who would otherwise be considered less than ideal research candidates, such as asymptomatic newborns. As we design more studies to assess risky but potentially curative treatments such as hematopoietic stem-cell transplantation, gene therapy, and embryonic stem-cell therapies for fatal, otherwise untreatable genetic diseases, a major challenge to investigators and regulatory and review agencies will be to maximize safety but also recognize the importance of including the very young, even those who are presymptomatic.
Dr. Weinberg reports having received an honorarium for consulting from Amgen.
Source Information
From the Division of Research Immunology and Bone Marrow Transplantation, Department of Pediatrics, Keck School of Medicine, University of Southern California, and the Children's Hospital of Los Angeles — both in Los Angeles.
References
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