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Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease

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Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease. / Hede, Eva ; Christiansen, Christine Bodelund; Würtz Heegaard, Christian et al.
I: Journal of Neurochemistry, Bind 156 , Nr. 3, 02.2021, s. 290–308.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Harvard

Hede, E, Christiansen, CB, Würtz Heegaard, C, Moos, T & Burkhart, A 2021, 'Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease', Journal of Neurochemistry, bind 156 , nr. 3, s. 290–308. https://doi.org/10.1111/jnc.14982

APA

Hede, E., Christiansen, C. B., Würtz Heegaard, C., Moos, T., & Burkhart, A. (2021). Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease. Journal of Neurochemistry, 156 (3), 290–308. https://doi.org/10.1111/jnc.14982

CBE

Hede E, Christiansen CB, Würtz Heegaard C, Moos T, Burkhart A. 2021. Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease. Journal of Neurochemistry. 156 (3):290–308. https://doi.org/10.1111/jnc.14982

MLA

Hede, Eva et al. "Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease". Journal of Neurochemistry. 2021, 156 (3). 290–308. https://doi.org/10.1111/jnc.14982

Vancouver

Hede E, Christiansen CB, Würtz Heegaard C, Moos T, Burkhart A. Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease. Journal of Neurochemistry. 2021 feb.;156 (3):290–308. doi: 10.1111/jnc.14982

Author

Hede, Eva ; Christiansen, Christine Bodelund ; Würtz Heegaard, Christian et al. / Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease. I: Journal of Neurochemistry. 2021 ; Bind 156 , Nr. 3. s. 290–308.

Bibtex

@article{b1718e6578f1470985560d730559b1d2,
title = "Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease",
abstract = "Treatment of many diseases affecting the central nervous system (CNS) is complicated by the inability of several therapeutics to cross the blood-brain barrier (BBB). Genetically modifying brain capillary endothelial cells (BCECs) denotes an approach to overcome the limitations of the BBB by turning BCECs into recombinant protein factories. This will result in protein secretion towards both the brain and peripheral circulation, which is particularly relevant in genetic diseases, like lysosomal storage diseases (LSD), where cells are ubiquitously affected both in the CNS and the periphery. Here we investigated transfection of primary rat brain capillary endothelial cells (rBCECs) for synthesis and secretion of recombinant NPC2, the protein deficient in the lysosomal cholesterol storage disease Niemann-Pick type C2. We demonstrate prominent NPC2 gene induction and protein secretion in 21% of BCECs in non-mitotic monocultures with a biological effect on NPC2 deficient fibroblasts as verified from changes in filipin III staining of cholesterol deposits. By comparison the transfection efficiency was 75% in HeLa-cells, known to persist in a mitotic state. When co-cultured with primary rat astrocytes in conditions with maintained BBB properties 7% BCECs were transfected, clearly suggesting that induction of BBB properties with polarized conditions of the non-mitotic BCECs influences the transfection efficacy and secretion directionality. In conclusion, non-viral gene therapy to rBCECs leads to protein secretion and signifies a method for NPC2 to target cells inside the CNS otherwise inaccessible due to the presence of the BBB. However, obtaining high transfection efficiencies is crucial in order to achieve sufficient therapeutic effects.",
keywords = "BBB, blood-brain barrier; BCECs, brain capillary endothelial cells; bNPC2, bovine Niemann Picks disease type C2 protein; BSA, bovine serum albumin; CTP-cAMP, 8-(4-Chlorophenylthio)adenosine 3′,5′-cyclic",
author = "Eva Hede and Christiansen, {Christine Bodelund} and {W{\"u}rtz Heegaard}, Christian and Torben Moos and Annette Burkhart",
year = "2021",
month = feb,
doi = "10.1111/jnc.14982",
language = "English",
volume = "156 ",
pages = "290–308",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell Publishing Ltd.",
number = "3",

}

RIS

TY - JOUR

T1 - Gene therapy to the blood-brain barrier with resulting protein secretion as a strategy for treatment of Niemann Picks type C2 disease

AU - Hede, Eva

AU - Christiansen, Christine Bodelund

AU - Würtz Heegaard, Christian

AU - Moos, Torben

AU - Burkhart, Annette

PY - 2021/2

Y1 - 2021/2

N2 - Treatment of many diseases affecting the central nervous system (CNS) is complicated by the inability of several therapeutics to cross the blood-brain barrier (BBB). Genetically modifying brain capillary endothelial cells (BCECs) denotes an approach to overcome the limitations of the BBB by turning BCECs into recombinant protein factories. This will result in protein secretion towards both the brain and peripheral circulation, which is particularly relevant in genetic diseases, like lysosomal storage diseases (LSD), where cells are ubiquitously affected both in the CNS and the periphery. Here we investigated transfection of primary rat brain capillary endothelial cells (rBCECs) for synthesis and secretion of recombinant NPC2, the protein deficient in the lysosomal cholesterol storage disease Niemann-Pick type C2. We demonstrate prominent NPC2 gene induction and protein secretion in 21% of BCECs in non-mitotic monocultures with a biological effect on NPC2 deficient fibroblasts as verified from changes in filipin III staining of cholesterol deposits. By comparison the transfection efficiency was 75% in HeLa-cells, known to persist in a mitotic state. When co-cultured with primary rat astrocytes in conditions with maintained BBB properties 7% BCECs were transfected, clearly suggesting that induction of BBB properties with polarized conditions of the non-mitotic BCECs influences the transfection efficacy and secretion directionality. In conclusion, non-viral gene therapy to rBCECs leads to protein secretion and signifies a method for NPC2 to target cells inside the CNS otherwise inaccessible due to the presence of the BBB. However, obtaining high transfection efficiencies is crucial in order to achieve sufficient therapeutic effects.

AB - Treatment of many diseases affecting the central nervous system (CNS) is complicated by the inability of several therapeutics to cross the blood-brain barrier (BBB). Genetically modifying brain capillary endothelial cells (BCECs) denotes an approach to overcome the limitations of the BBB by turning BCECs into recombinant protein factories. This will result in protein secretion towards both the brain and peripheral circulation, which is particularly relevant in genetic diseases, like lysosomal storage diseases (LSD), where cells are ubiquitously affected both in the CNS and the periphery. Here we investigated transfection of primary rat brain capillary endothelial cells (rBCECs) for synthesis and secretion of recombinant NPC2, the protein deficient in the lysosomal cholesterol storage disease Niemann-Pick type C2. We demonstrate prominent NPC2 gene induction and protein secretion in 21% of BCECs in non-mitotic monocultures with a biological effect on NPC2 deficient fibroblasts as verified from changes in filipin III staining of cholesterol deposits. By comparison the transfection efficiency was 75% in HeLa-cells, known to persist in a mitotic state. When co-cultured with primary rat astrocytes in conditions with maintained BBB properties 7% BCECs were transfected, clearly suggesting that induction of BBB properties with polarized conditions of the non-mitotic BCECs influences the transfection efficacy and secretion directionality. In conclusion, non-viral gene therapy to rBCECs leads to protein secretion and signifies a method for NPC2 to target cells inside the CNS otherwise inaccessible due to the presence of the BBB. However, obtaining high transfection efficiencies is crucial in order to achieve sufficient therapeutic effects.

KW - BBB, blood-brain barrier; BCECs, brain capillary endothelial cells; bNPC2, bovine Niemann Picks disease type C2 protein; BSA, bovine serum albumin; CTP-cAMP, 8-(4-Chlorophenylthio)adenosine 3′,5′-cyclic

U2 - 10.1111/jnc.14982

DO - 10.1111/jnc.14982

M3 - Journal article

C2 - 32072649

VL - 156

SP - 290

EP - 308

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 3

ER -