Transport of Arylsulfatase A across the Blood-Brain Barrier in Vitro

Matthes, Frank; Wölte, Philipp; Böckenhoff, Annika; Hüwel, Sabine; Schulz, M; Hyden, Pia; Fogh, Jørgen; Gieselmann, Volkmar; Galla, Hans‐Joachim; Matzner, Ulrich

doi:10.1074/jbc.m110.189381

Cited by 25 publications

(22 citation statements)

References 36 publications

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“…The overall low and size‐dependent permeability to FITC‐dextrans further confirmed the barrier integrity of the BBB constructs in our model. Remarkably, we achieved extremely low permeabilities to FITC‐dextrans that were comparable to previously reported in vivo values (Shi et al, ; Yuan et al, ) and the in vitro data from transwell models with high TEER values (Cramer, ; Matthes et al, ). Our results were around two to three orders of magnitude lower than those reported from existing microfluidic BBB models (Booth and Kim, ).…”

Section: Resultssupporting

confidence: 89%

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Wang

Abaci

Shuler

2016

Biotech & Bioengineering

416

405

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Efficient delivery of therapeutics across the neuroprotective blood-brain barrier (BBB) remains a formidable challenge for central nervous system drug development. Highfidelity in vitro models of the BBB could facilitate effective early screening of drug candidates targeting the brain. In this study, we developed a microfluidic BBB model that is capable of mimicking in vivo BBB characteristics for a prolonged period and allows for reliable in vitro drug permeability studies under recirculating perfusion. We derived brain microvascular endothelial cells (BMECs) from human induced pluripotent stem cells (hiPSCs) and cocultured them with rat primary astrocytes on the two sides of a porous membrane on a pumpless microfluidic platform for up to 10 days. The microfluidic system was designed based on the blood residence time in human brain tissues, allowing for medium recirculation at physiologically relevant perfusion rates with no pumps or external tubing, meanwhile minimizing wall shear stress to test whether shear stress is required for in vivo-like barrier properties in a microfluidic BBB model. This BBB-on-a-chip model achieved significant barrier integrity as evident by continuous tight junction formation and in vivo-like values of trans-endothelial electrical resistance (TEER). The TEER levels peaked above 4000 V Á cm 2 on day 3 on chip and were sustained above 2000 V Á cm 2 up to 10 days, which are the highest sustained TEER values reported in a microfluidic model. We evaluated the capacity of our microfluidic BBB model to be used for drug permeability studies using large molecules (FITC-dextrans) and model drugs (caffeine, cimetidine, and doxorubicin). Our analyses demonstrated that the permeability coefficients measured using our model were comparable to in vivo values. Our BBB-on-a-chip model closely mimics physiological BBB barrier functions and will be a valuable tool for screening of drug candidates. The residence time-based design of a microfluidic platform will enable integration with other organ modules to simulate multi-organ interactions on drug response.

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Section: Resultssupporting

confidence: 89%

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Wang

Abaci

Shuler

2016

Biotech & Bioengineering

416

405

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“…Enhanced central nervous system uptake of rhGAA in the current experiments correlated with increased CI-MPR expression, which has been postulated as a mechanism for circumventing the blood-brain barrier during ERT in lysosomal storage disorders [26]. Recently an in vitro model of the blood-brain barrier revealed that arylsulfatase A uptake across the barrier was partially dependent upon CI-MPR, further validating the role of CI-MPR in the entry of lysosomal enzymes into the central nervous system [34]. …”

Section: Discussionsupporting

confidence: 71%

β2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease

Koeberl

Dai

et al. 2012

Molecular Genetics and Metabolism

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Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes.

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“…4 C ). Recently, an in vitro model of the blood‐brain barrier revealed that arylsulfatase A uptake was partially dependent on CI‐MPR (52). These data support the possibility that β2‐agonists might be a useful adjunctive therapy for other lysosomal storage disorders such as mucopolysaccharidoses that feature severe brain involvement (53).…”

Section: Discussionmentioning

confidence: 99%

Adjunctive β2‐agonists reverse neuromuscular involvement in murine Pompe disease

Sun

Nilsson

et al. 2012

FASEB j.

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Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.

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Transport of Arylsulfatase A across the Blood-Brain Barrier in Vitro

Cited by 25 publications

References 36 publications

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

Microfluidic blood–brain barrier model provides in vivo‐like barrier properties for drug permeability screening

β2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease

Adjunctive β2‐agonists reverse neuromuscular involvement in murine Pompe disease

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