Early umbilical cord blood-derived stem cell transplantation does not prevent neurological deterioration in mucopolysaccharidosis type III

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

Neonatal bone marrow transplantation in MPS IIIA mice

Patients with some neurological lysosomal storage disorders (LSD) exhibit improved clinical signs following bone marrow transplantation (BMT). The failure of mucopolysaccharidosis (MPS) type IIIA patients and adult mice with the condition to respond to this treatment may relate to factors such as impaired migration of donor-derived cells into the brain, insufficient enzyme production and/or secretion by the donor-derived microglial cells, or the age at which treatment is initiated. To explore these possibilities, we treated neonatal MPS IIIA mice with whole unfractionated bone marrow and observed that nucleated blood cell reconstitution occurred to a similar degree in MPS IIIA mice receiving green fluorescent protein (GFP)-expressing normal (treatment group) or MPS IIIA-GFP marrow (control group) and normal mice receiving normal-GFP marrow (control group). Further, similar distribution patterns of GFP+ normal or MPS IIIA donor–derived cells were observed throughout the MPS IIIA mouse brain. We demonstrate that N-sulfoglucosamine sulfohydrolase (SGSH), the enzyme deficient in MPS IIIA, is produced and secreted in a manner proportional to that of other lysosomal enzymes. However, despite this, overall brain SGSH activity was unchanged in MPS IIIA mice treated with normal marrow and the lysosomal storage burden in whole brain homogenates did not decrease, most likely due to donor-derived cells comprising <0.24% of total recipient brain cells in all groups. This suggests that the failure of MPS IIIA patients and mice to respond to BMT may occur as a result of insufficient donor-derived enzyme production and/or uptake by host brain cells.Adeline A Lau, N. Jannah Shamsani, Leanne K. Winner, Sofia Hassiotis, Barbara M. King, John J. Hopwood, Kim M. Hemsle

Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB

Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α–N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood–brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood–brain barrier, the fusion protein (“enzyme”) in artificial cerebrospinal fluid (“vehicle”) was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1–28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [β-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, β-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and β-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB