scholarly journals Stem Cell Transplantation for Adult-Onset Krabbe Disease: Report of a Case

2012 ◽  
pp. 57-59 ◽  
Author(s):  
Madeleine E. Sharp ◽  
Cornelia Laule ◽  
Stephen Nantel ◽  
Burkhard Mädler ◽  
Ritu B. Aul ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Krabbe Disease ◽  
Adult Onset

Hematopoietic Stem Cell Transplantation for Late-Onset Krabbe Disease

2015 ◽  
Vol 46 (S 01) ◽  
Author(s):  
A. Bley ◽  
U. Löbel ◽  
M. Nickel ◽  
A. Ohlenbusch ◽  
J. Denecke ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Late Onset ◽  
Krabbe Disease ◽  
Hematopoietic Stem

Stem cell transplantation in Krabbe disease

Neurology ◽  
2017 ◽  
Vol 89 (13) ◽  
pp. 1318-1319 ◽  
Author(s):  
William D. Graf
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Krabbe Disease

scholarly journals Can early treatment of twitcher mice with high dose AAVrh10-GALC eliminate the need for BMT?

Bioimpacts ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 135-146
Author(s):  
Mohammad A Rafi ◽  
Paola Luzi ◽  
David A Wenger
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Viral Vector ◽  
Krabbe Disease ◽  
High Dose ◽  
Restriction Enzyme Digestion ◽  
Hematopoietic Stem ◽  
Galc Gene

Introduction: Krabbe disease (KD) is an autosomal recessive disorder caused by mutations in the galactocerebrosidase (GALC) gene resulting in neuro-inflammation and defective myelination in the central and peripheral nervous systems. Most infantile patients present with clinical features before six months of age and die before two years of age. The only treatment available for pre-symptomatic or mildly affected individuals is hematopoietic stem cell transplantation (HSCT). In the animal models, combining bone marrow transplantation (BMT) with gene therapy has shown the best results in disease outcome. In this study, we examine the outcome of gene therapy alone. Methods: Twitcher (twi) mice used in the study, have a W339X mutation in the GALC gene. Genotype identification of the mice was performed shortly after birth or post-natal day 1 (PND1), using polymerase chain reaction on the toe clips followed by restriction enzyme digestion and electrophoresis. Eight or nine-day-old affected mice were used for gene therapy treatment alone or combined with BMT. While iv injection of 4 × 1013 gc/kg of body weight of viral vector was used originally, different viral titers were also used without BMT to evaluate their outcomes. Results: When the standard viral dose was increased four- and ten-fold (4X and 10X) without BMT, the lifespans were increased significantly. Without BMT the affected mice were fertile, had the same weight and appearance as wild type mice and had normal strength and gait. The brains showed no staining for CD68, a marker for activated microglia/macrophages, and less astrogliosis than untreated twi mice. Conclusion: Our results demonstrate that, it may be possible to treat human KD patients with high dose AAVrh10 without blood stem cell transplantation which would eliminate the side effects of HSCT.

scholarly journals β-Galactosylceramidase Deficiency Causes Bone Marrow Vascular Defects in an Animal Model of Krabbe Disease

2019 ◽  
Vol 21 (1) ◽  
pp. 251
Author(s):  
Mirella Belleri ◽  
Daniela Coltrini ◽  
Marco Righi ◽  
Cosetta Ravelli ◽  
Sara Taranto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Krabbe Disease ◽  
Microscopy Imaging ◽  
Hematopoietic Stem

Krabbe disease (KD) is an autosomal recessive sphingolipidosis caused by the deficiency of the lysosomal hydrolase β-galactosylceramidase (GALC). Oligodendroglia degeneration and demyelination of the nervous system lead to neurological dysfunctions which are usually lethal by two years of age. At present, the only clinical treatment with any proven efficacy is hematopoietic stem-cell transplantation, which is more effective when administered in the neonatal period to presymptomatic recipients. Bone marrow (BM) sinusoidal endothelial cells (SECs) play a pivotal role in stem cell engraftment and reconstitution of hematopoiesis. Previous observations had shown significant alterations of microvascular endothelial cells in the brain of KD patients and in Galc mutant twitcher mice, an authentic model of the disease. In the present study, we investigated the vascular component of the BM in the femurs of symptomatic homozygous twitcher mice at postnatal day P36. Histological, immunohistochemical, and two-photon microscopy imaging analyses revealed the presence of significant alterations of the diaphyseal BM vasculature, characterized by enlarged, discontinuous, and hemorrhagic SECs that express the endothelial marker vascular endothelial growth factor receptor-2 (VEGFR2) but lack platelet/endothelial cell adhesion molecule-1 (CD31) expression. In addition, computer-aided image analysis indicates that twitcher CD31−/VEGFR2+ SECs show a significant increase in lumen size and in the number and size of endothelial gaps compared to BM SECs of wild type littermates. These results suggest that morphofunctional defects in the BM vascular niche may contribute to the limited therapeutic efficacy of hematopoietic stem-cell transplantation in KD patients at symptomatic stages of the disease.

scholarly journals Long-Term Neurodevelopmental Outcomes of Hematopoietic Stem Cell Transplantation for Late-Infantile Krabbe Disease

Blood ◽  
2020 ◽  
Author(s):  
Isabel C Yoon ◽  
Nicholas A Bascou ◽  
Michele D Poe ◽  
Paul Szabolcs ◽  
Maria L Escolar
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Symptom Onset ◽  
Disease Onset ◽  
Krabbe Disease ◽  
Hematopoietic Stem ◽  
Prospective Longitudinal

Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in galactocerebrosidase. The only effective treatment is hematopoietic stem cell transplantation (HSCT). Approximately 85% of Krabbe cases are the infantile subtypes, among which ~20% are late-infantile. Prior studies demonstrated that HSCT is effective for early-infantile patients (0 - 6 months of age) transplanted while asymptomatic, compared to those transplanted while symptomatic. However, no studies evaluated the efficacy of HSCT for late-infantile patients (6 - 36 months). In this prospective, longitudinal study, patients were evaluated at a single site following a standardized protocol. Survival analysis was performed using the Kaplan-Meier method. Differences between groups were estimated using Mixed Regression models to account for within person repeated measures. Nineteen late-infantile patients underwent HSCT (1997 - 2020). Compared to untreated patients, transplanted patients had a longer survival probability and improved cognitive and language function. Gross and fine motor development were most affected with variable results. Asymptomatic patients benefitted the most from transplantation with normal to near-normal development in all domains and some gross motor delays. Among symptomatic patients, those with disease onset > 12 months of age had better cognitive outcomes than untreated patients. Those with disease onset £ 12 months were comparable to untreated patients. We found that HSCT prolongs the lifespan and improves the functional abilities of late-infantile Krabbe patients, particularly for those transplanted before symptom onset. In addition, our findings support prior literature that reclassifies late-infantile Krabbe disease to be symptom onset 12 to 36 months of age.

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