Back to Search
Start Over
Clathrin-Mediated Endocytosis Is Impaired in Type A–B Niemann–Pick Disease Model Cells and Can Be Restored by ICAM-1-Mediated Enzyme Replacement
- Source :
- Molecular Pharmaceutics
- Publication Year :
- 2014
- Publisher :
- American Chemical Society, 2014.
-
Abstract
- Drugs often use endocytosis to achieve intracellular delivery, either by passive uptake from the extracellular fluid or by active targeting of cell surface features such as endocytic receptors. An example is enzyme replacement therapy, a clinically practiced treatment for several lysosomal storage diseases where glycosylated recombinant enzymes naturally target the mannose-6-phosphate receptor and are internalized by clathrin mediated endocytosis (CME). However, lysosomal substrate accumulation, a hallmark of these diseases, has been indirectly linked to aberrant endocytic activity. These effects are poorly understood, creating an obstacle to therapeutic efficiency. Here we explored endocytic activity in fibroblasts from patients with type A Niemann-Pick disease, a lysosomal storage disease characterized by acid sphingomyelinase (ASM) deficiency. The uptake of fluid phase markers and clathrin-associated ligands, formation of endocytic structures, and recruitment of intracellular clathrin to ligand binding sites were all altered, demonstrating aberrant CME in these cells. Model polymer nanocarriers targeted to intercellular adhesion molecule-1 (ICAM-1), which are internalized by a clathrin-independent route, enhanced the intracellular delivery of recombinant ASM more than 10-fold compared to free enzyme. This strategy reduced substrate accumulation and restored clathrin endocytic activity to wild-type levels. There appears to be a relationship between lysosomal storage and diminished CME, and bypassing this pathway by targeting ICAM-1 may enhance future therapies for lysosomal storage diseases.
- Subjects :
- Polymers
Endocytic cycle
Pharmaceutical Science
Ligands
Mice
0302 clinical medicine
Drug Discovery
Lysosomal storage disease
Niemann-Pick Diseases
0303 health sciences
Drug Carriers
Pinocytosis
Antibodies, Monoclonal
Intercellular Adhesion Molecule-1
type A−B Niemann−Pick disease
Lipids
Endocytosis
Recombinant Proteins
Cell biology
Nanomedicine
Phenotype
Sphingomyelin Phosphodiesterase
Biochemistry
Molecular Medicine
Acid sphingomyelinase
Niemann–Pick disease
medicine.drug
clathrin endocytosis
Biology
Clathrin
Article
CAM-mediated endocytosis
03 medical and health sciences
medicine
Animals
Humans
Enzyme Replacement Therapy
030304 developmental biology
Binding Sites
Cell Membrane
Receptor-mediated endocytosis
Fibroblasts
medicine.disease
ICAM-1-targeted nanocarriers
biology.protein
Microscopy, Electron, Scanning
Nanoparticles
Lysosomes
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 15438392 and 15438384
- Volume :
- 11
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmaceutics
- Accession number :
- edsair.doi.dedup.....3b43159113468926c1290d654306a32e