Early Umbilical Cord Blood-Derived Stem Cell Transplantation Does Not Prevent Neurological Deterioration in Mucopolysaccharidosis Type III

Abstract

Mucopolysaccharidosis type III (MPS III), or Sanfilippo disease, is a neurodegenerative lysosomal storage disease (LSD) caused by defective lysosomal degradation of heparan sulfate (HS). No effective disease-modifying therapy is yet available. In contrast to some other neuronopathic LSDs, bone marrow-derived hematopoietic stem cell transplantation (HSCT) fails to prevent neurological deterioration in MPS III patients. We report on the 5-year outcome of early transplantation, i.e., before onset of clinical neurological disease, in combination with the use of umbilical cord blood-derived hematopoietic stem cells (UCBT), in two MPS III patients. Both patients had a normal developmental quotient at the time of UCBT. One patient had a combination of mutations predicting a classical severe phenotype (MPS IIIA), and one patient (MPS IIIB) had mutations predicting a very attenuated phenotype. Transplantation was uncomplicated with full engraftment of donor cells in both.Both patients showed progressive neurological deterioration with regression of cognitive skills and behavioral disturbances during 5 years after successful UCBT, comparable to the natural history of patients with the same combination of mutations. The concentration of HS in CSF in the patient with the attenuated phenotype of MPS IIIB 2 years after UCBT was very high and in the range of untreated MPS III patients.We conclude that the course of cognitive development, behavioral problems, and absence of biochemical correction in CSF demonstrate the absence of relevant effect of UCBT in MPS III patients, even when performed before clinical onset of CNS disease.

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

“…Hematopoietic stem cell transplantation (HSCT) was the first treatment, applied with success to the most severe form of mucopolysaccharidosis (MPS) type I (Hurler) [3]. It was also employed in smaller numbers of patients with MPS II, III, IV and VI with controversial results [4][5][6][7][8][9][10][11][12][13]. Recent evidence suggests HSCT as an acceptable treatment option for MPS II [12][13][14].…”

Potential use of stem cells as a therapy for cystinosis

“…Same results have been obtained for patients affected with Krabbe disease, a demyelinating disorder caused by a deficiency of galactosylceramidase if early transplantation is performed [20][21][22]. Nonetheless, for some LSDs (Sanfilippo or GM1 gangliosidosis), HSPC transplantation did not show clinical benefit [23,24]. The reason for unsuccessful HSPC transplant is unclear.…”

“…The reason for unsuccessful HSPC transplant is unclear. In the case of Sanfilippo, it is suggested that the donor-derived microglia cells secrete insufficient amounts of enzymes for cross-correction of the neuronal tissue [24].…”

Neuronopathic Types of Mucopolysaccharidoses: Pathogenesis and Emerging Treatments

“…Однако трудности подбора доно-ра, развитие реакции «трансплантат против хозяина» и осложнений миелоаблативной терапии с высоким риском летального исхода заставляют искать альтер-нативные терапевтические подходы [9,10,34]. Опыт трансплантации гемопоэтических стволовых клеток у пациентов с МПС II и III свидетельствует о неэффектив-ности этого метода лечения в отношении нейродегене-ративного процесса [9,35,36]. Клеточная и генная терапия Еще одним разрабатываемым методом лечения ней-ронопатических МПС является генная терапия, способная обеспечить непрерывное поступление терапевтического белка в головной мозг.…”