Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in -mannosidosis mice

Biochemical Institute, University of Kiel, Kiel, Germany.
Human Molecular Genetics (Impact Factor: 6.39). 09/2008; 17(22):3437-45. DOI: 10.1093/hmg/ddn237
Source: PubMed


Despite the progress in the treatment of lysosomal storage disorders (LSDs) mainly by enzyme replacement therapy, only limited success was reported in targeting the appropriate lysosomal enzyme into the brain. This prevents efficient clearance of neuronal storage, which is present in many of these disorders including alpha-mannosidosis. Here we show that the neuropathology of a mouse model for alpha-mannosidosis can be efficiently treated using recombinant human alpha-mannosidase (rhLAMAN). After intravenous administration of different doses (25-500 U/kg), rhLAMAN was widely distributed among tissues, and immunohistochemistry revealed lysosomal delivery of the injected enzyme. Whereas low doses (25 U/kg) led to a significant clearance (<70%) in visceral tissues, higher doses were needed for a clear effect in central and peripheral nervous tissues. A distinct reduction (<50%) of brain storage required repeated high-dose injections (500 U/kg), whereas lower doses (250 U/kg) were sufficient for clearance of stored substrates in peripheral neurons of the trigeminal ganglion. Successful transfer across the blood-brain barrier was evident as the injected enzyme was found in hippocampal neurons, leading to a nearly complete disappearance of storage vacuoles. Importantly, the decrease in neuronal storage in the brain correlated with an improvement of the neuromotor disabilities found in untreated alpha-mannosidosis mice. Uptake of rhLAMAN seems to be independent of mannose-6-phosphate receptors, which is consistent with the low phosphorylation profile of the enzyme. These data suggest that high-dose injections of low phosphorylated enzymes might be an interesting option to efficiently treat LSDs with CNS involvement.

Download full-text


Available from: Judith Blanz, Oct 14, 2015
1 Follower
24 Reads
  • Source
    • "Disease Animal model Enzyme deficient Enzyme activity in the brain Improved neuropathology References Alpha-mannosidosis Mice alpha-D-mannosidase Yes Yes [26] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here we hypothesized that the water-soluble lysosomal enzymes may cross the blood-brain-barrier and reach the brain using the mechanism of unspecific fluid-phase endocytosis. We also highlight studies that show that, at higher serum concentrations, a fraction of these proteins can reach the brain after intravenous injection, and we suggest some experiments to study this hypothesis. Finally we discuss the implications of this for treatments such as enzyme replacement of lysosomal storage disorders.
    Medical Hypotheses 02/2014; 82(4). DOI:10.1016/j.mehy.2014.01.029 · 1.07 Impact Factor
  • Source
    • "At present, MPSII patients are treated with an infusion of 0.5 mg/kg recombinant human IDS once a week (28–30); here, we show that in juvenile mice, the systemically infused low dose of 1.2 mg/kg human IDS administered once every 7 days for short and for prolonged treatment periods is sufficient to ameliorate and apparently prevent progression of the CNS defects in these MPSII mice. Thus one of the important observations of the present study is that as opposed to much higher doses of other enzymes needed for ERT (such as β-glucuronidase in MPSVII mice, arylsulfatase A in metachromatic leukodystrophy mice and α-mannosidase in α-mannosidasis mice) to obtain only minor improvements in the CNS phenotypes (26,27,31), here we have a scenario in which a dose that is very close to that used already in the clinic is sufficient to improve the CNS phenotype of MPSII mice. Remarkably, a clear improvement in the disease phenotype is also seen in the 7-month-old mice when a high dose (10 mg/kg) of IDS was administered once every 7 days for 3 months, showing that even when the CNS impairment is clearly manifested, ERT can be effective to ameliorate the disease. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mucopolysaccharidosis type II (MPSII), or Hunter syndrome, is a devastating disorder associated with a shortened life expectancy. Patients affected by MPSII have a variety of symptoms that affect all organs of the body and may include progressive cognitive impairment. MPSII is due to inactivity of the enzyme iduronate-2-sulfatase (IDS), which results in the accumulation of storage material in the lysosomes, such as dermatan and heparan sulfates, with consequent cell degeneration in all tissues including, in the severe phenotype, neurodegeneration in the central nervous system (CNS). To date, the only treatment available is systemic infusion of IDS, which ameliorates exclusively certain visceral defects. Therefore, it is important to simultaneously treat the visceral and CNS defects of the MPSII patients. Here, we have developed enzyme replacement therapy (ERT) protocols in a mouse model that allow the IDS to reach the brain, with the substantial correction of the CNS phenotype and of the neurobehavioral features. Treatments were beneficial even in adult and old MPSII mice, using relatively low doses of infused IDS over long intervals. This study demonstrates that CNS defects of MPSII mice can be treated by systemic ERT, providing the potential for development of an effective treatment for MPSII patients.
    Human Molecular Genetics 09/2010; 19(24):4871-85. DOI:10.1093/hmg/ddq420 · 6.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Developing therapies for the brain is perhaps the greatest challenge facing modern medicine today. While a great many potential therapies show promise in animal models, precious few make it to approval or are even studied in human patients. The particular challenges to the translation of neurotherapeutics to the clinic are many, but a major barrier is difficulty in delivering therapeutics into the brain. The goal of this workshop was to present ways to deliver therapeutics to the brain, including the limitations of each method, and describe ways to track their delivery, safety, and efficacy. Solving the problem of delivery will aid translation of therapeutics for patients suffering from neurodegeneration and other disorders of the brain.
    Drug Delivery and Translational Research 06/2012; 2(3). DOI:10.1007/s13346-012-0068-0
Show more