Impact of chemical modification of sulfamidase on distribution to brain interstitial fluid and to CSF after an intravenous administration in awake, freely-moving rats

Abstract

Mucopolysaccharidosis III A (MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. The disorder results in accumulation of heparan sulfate, lysosomal enlargement and cellular and organ dysfunction. Patients exhibit progressive neurodegeneration and behavioral problems and no treatment is currently available. Enzyme replacement therapy is explored as potential treatment strategy for MPS IIIA patients and to modify the disease, sulfamidase must reach the brain. The glycans of recombinant human sulfamidase (rhSulfamidase) can be chemically modified to generate CM-rhSulfamidase. The chemical modification reduced the affinity to the cation-independent mannose-6-phosphate receptor with the aim a prolonged higher concentration in circulation and thus at the blood brain barrier. The pharmacokinetic properties in serum and the distribution to brain and to cerebrospinal fluid (CSF) of chemically modified recombinant human sulfamidase (CM-rhSulfamidase) were studied and compared to those of rhSulfamidase, after a single intravenous (i.v.) 30 mg/kg dose in awake, freely-moving male Sprague Dawley rats. Distribution to brain was studied by microdialysis of the interstitial fluid in prefrontal cortex and by repeated intra-individual CSF sampling from the cisterna magna. Push-pull microdialysis facilitated sampling of brain interstitial fluid to determine large molecule concentrations in awake, freely-moving male Sprague Dawley rats. Together with repeated serum and CSF sampling, push-pull microdialysis facilitated determination of CM-rhSulfamidase and rhSulfamidase kinetics after i.v. administration by non-compartments analysis and by a population modelling approach. Chemical modification increased the area under the concentration versus time in serum, CSF and brain interstitial fluid at least 7-fold. The results and the outcome of a population modelling approach of the concentration versus time data indicated that both compounds pass the BBB with an equilibrium established fairly rapid after administration. We suggest that prolonged high serum concentrations facilitated high brain interstitial fluid concentrations, which could be favorable to reach various target cells in the brain.

Targeting the central nervous system in lysosomal storage diseases: Strategies to deliver therapeutics across the blood-brain barrier

“…This approach has been tested in MPS VII 48,49 and MPS IIIA [50][51][52] murine models, showing significant reduction in CNS lysosomal storage biomarkers [48][49][50][51][52] .…”

Design and simulation of a neural interface based on a microfluidic flexible interconnection cable for chemical delivery

“…In our study, a neural interface is designed to be implanted in rodents, mainly Sprague-Dawley rats, to verify the device. The total volume of cerebrospinal fluid (CSF) in adult SD rats is about 400 µL [17]. And reproduction rate of CSF is 1.4 to 3.38 µL/min [17,18].…”

“…The total volume of cerebrospinal fluid (CSF) in adult SD rats is about 400 µL [17]. And reproduction rate of CSF is 1.4 to 3.38 µL/min [17,18]. The desired design values take into account the reproduction rate of CSF.…”

Investigating brain uptake of a non-targeting monoclonal antibody after intravenous and intracerebroventricular administration

“…Both methods bear the risk of erroneous determination of brain concentrations in parenchyma. As an alternative approach, such as large pore membrane microdialysis ( Chang et al, 2018 ; Janson et al, 2020 ) and open flow perfusion ( Le Prieult et al, 2021 ) have been successfully applied to measure drug exposure in the interstitial fluid of different brain regions in nonclinical studies. In clinical studies, the PK is sampled from the cerebrospinal fluid (CSF) as a surrogate of brain exposure ( Pestalozzi and Brignoli, 2000 ; Rubenstein et al, 2007 ; Stemmler et al, 2007 ), however this is not appropriately reflecting the drug concentration in the ISF of the brain ( Pardridge, 2016 ).…”