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Umbilical cord blood therapy of Krabbe's disease

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    Umbilical cord blood therapy of Krabbe's disease

    Umbilical Cord Blood therapy of Krabbe's Disease: Lessons and Questions
    Wise Young, Ph.D., M.D.
    W. M. Keck Center for Collaborative Neuroscience
    Rutgers University, Piscataway, New Jersey 08854
    31 July 2005

    In May 2005, the New England Journal of Medicine published a landmark study from the University of North Carolina and Duke University. Authored by Maria L. Escolar and colleagues, the study reported a treatment that saves the lives of children with Krabbe's disease, a rare autosomal recessive genetic disorder characterized by loss of the enzyme galactocerebrosidase which is necessary for normal myelination of brain, spinal cord, and peripheral nerves. Galactolipids accumulate in myelin, leading to inflammation and demyelination. Symptoms start appearing before 6 months. Infants become irritable, stop developing, become deaf and blind, have seizures and die. Parents have to watch their children die (Source).

    What is the treatment that saves their lives? Myeloablation (destruction of their bone marrow) and umbilical cord blood administration. As described in the following abstract, Escobar, et al. treated 12 asymptomatic young infants (12-44 days old) and 14 symptomatic older infants (142-352 days old) and followed them for 4 months to 6 years. All the children received myeloablative therapies to eliminate their bone marrows and infusions of matched umbilical cord blood from unrelated donors. The umbilical cord blood engrafted in all the children. In children that were treated early, before symptoms began, 100% survived a median to 3 years. In contrast, in the children who were treated after symptoms began, only 43% survived. Those children who survived showed progressive central myelination, gains of motor, cognitive, and language skills. However, children who received treatment after the symptoms had started showed little or not neurological improvement.

    Although there is clearly a need to replicate this study and confirm the results, the results are striking in this devastating disease. Given the lack of any other treatment for this condition and the almost invariably fatal outcome of this disease, myeloablation plus umbilical cord blood treatment will almost certainly be given to infants with suspected Krabbe's disease. While the mechanisms by which the treatment was beneficial in the disease is not clear, the results showed clearly that the umbilical cord blood was preventing the disease and did not reverse the neurological deficits once they started. Three other results of this study are noteworthy.

    First, all the children underwent myeloablative therapy with busulfan, cyclophosphamide, and antithymocyte globulin and then received transplants of partilly or fully HLA-matched cord-blood cells from unrelated donors, followed by cylcosporine and steroids to prevent graft-versus-host disease. Of the 25 children in the study, 22 received their umbilical cord blood transplants at Duke University. In all the children, the transplanted umbilical cord blood stem cells engrafted and essentiall replaced the hematopoietic cells of the children. This is clearly not a trivial therapy but also a remarkably successful one in that the umbilical cord blood engrafted in all children with no deaths.

    Second, although the asymptomic children showed gains of development and cerebral function, the treatment is by no means a cure. The successfully treated children continue to have retarded cognitive development. However, compared to the symptomatic children, they were much better off. The surviving symptomatic children had motor function equivalent to that of a one year old child. Early diagnosis and treatment are clearly desirable. Time is of the essence. Infants must be screened and treated for the disease before neurological symptoms are apparent.

    Third, although there is much speculation that umbilical cord blood stem cells may be able to act as stem cells and promote remyelination, this is apparently not the case in the symptomatic children who received the umbilical cord blood. MRI evidence suggested evidence of brain atrophy and worsening of demyelination with time. Over half died within the 3-6 year followup period. Thus, while the treatment may have retarded the disease somewhat, it did not reverse the disease in older symptomatic children.

    Although this study is very important and rightly heralded by the some as a breakthrough for use of umbilical cord blood therapy (Source), the study does not provide clear evidence that umbilical cord blood remyelinate the brain in this disease. Yagi, et al. (2005) had reported that bone marrow stem cell transplants may have some beneficial effects in the disease in mice but did not find that umbilical cord blood cells remyelinated either the central or peripheral nervous system.

    Compared to bone marrow stem cell transplants from unrelated donors, umbilical cord blood is more available, easier to match, imposes less risk of severe graft versus host disease (GVHD) where transplanted white blood cells attack the host. Umbilical cord blood appears to stop the progressive demyelination that occurs in the disease (Source). It would be very interesting to see whether these children have remyelination of their peripheral nerves and brain by the transplanted umbilical cord blood cells.

    Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W and Kurtzberg J (2005). Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med 352: 2069-81. BACKGROUND: Infantile Krabbe's disease produces progressive neurologic deterioration and death in early childhood. We hypothesized that transplantation of umbilical-cord blood from unrelated donors before the development of symptoms would favorably alter the natural history of the disease among newborns in whom the disease was diagnosed because of a family history. We compared the outcomes among these newborns with the outcomes among infants who underwent transplantation after the development of symptoms and with the outcomes in an untreated cohort of affected children. METHODS: Eleven asymptomatic newborns (age range, 12 to 44 days) and 14 symptomatic infants (age range, 142 to 352 days) with infantile Krabbe's disease underwent transplantation of umbilical-cord blood from unrelated donors after myeloablative chemotherapy. Engraftment, survival, and neurodevelopmental function were evaluated longitudinally for four months to six years. RESULTS: The rates of donor-cell engraftment and survival were 100 percent and 100 percent, respectively, among the asymptomatic newborns (median follow-up, 3.0 years) and 100 percent and 43 percent, respectively, among the symptomatic infants (median follow-up, 3.4 years). Surviving patients showed durable engraftment of donor-derived hematopoietic cells with restoration of normal blood galactocerebrosidase levels. Infants who underwent transplantation before the development of symptoms showed progressive central myelination and continued gains in developmental skills, and most had age-appropriate cognitive function and receptive language skills, but a few had mild-to-moderate delays in expressive language and mild-to-severe delays in gross motor function. Children who underwent transplantation after the onset of symptoms had minimal neurologic improvement. CONCLUSIONS: Transplantation of umbilical-cord blood from unrelated donors in newborns with infantile Krabbe's disease favorably altered the natural history of the disease. Transplantation in babies after symptoms had developed did not result in substantive neurologic improvement. Program for Neurodevelopmental Function in Rare Disorders, Clinical Center for the Study of Development and Learning, University of North Carolina at Chapel Hill, Chapel Hill 27599-7255, USA.
    Yagi T, Matsuda J, Tominaga K and Suzuki K (2005). Hematopoietic cell transplantation ameliorates clinical phenotype and progression of the CNS pathology in the mouse model of late onset Krabbe disease. J Neuropathol Exp Neurol 64: 565-75. Krabbe disease is a genetic demyelinating disease caused by a deficiency of galactosylceramidase. The majority of cases are of infantile onset with rapid clinical course. A rare late onset form with milder clinical symptoms also exists. The latter form has been reported to respond well to the bone marrow transplantation (BMT) therapy. We tested whether the BMT could be an effective therapy for the mouse model of the late onset form, saposin-A-/- (SAP-A-/-) mice. We used green fluorescent protein transgenic mice as the donors. Chimeric SAP-A-/- mice that received BMT showed very little evidence of neurologic symptoms. At postnatal day 190 when severe demyelination was evident in naive SAP-A-/- mice, demyelination was virtually absent in the brain of chimeric SAP-A-/- mice. Presence of residual enzyme activity, at the time of rapid myelination in SAP-A-/- mice, appears to limit initial inflammatory responses and macrophage infiltration, thereby preventing progression of demyelination in the CNS in SAP-A-/- mice. In contrast, the peripheral nerves showed features of hypertrophic neuropathy with hypomyelination and onion bulb formation, suggesting that there are different cellular responses to the BMT in the CNS and PNS. Department of Pathology and Laboratory Medicine , University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
    Last edited by Wise Young; 1 Aug 2005, 3:43 AM.

    my friend's daughter have Krabbe Disease

    I live in Taiwan, and my friend's daughter because had Krabbe Disease.Have on the forum to see Umbilical Cord Blood therapy of Krabbe's Disease, would like to request the assistance of the Wise Young.Can you give some recommendations on treatment.In trouble your e-mail contact (joyce.su1213 @