Systemic enzyme delivery by blood-brain barrier-penetrating SapC-DOPS nanovesicles for treatment of neuronopathic Gaucher disease
Ying Sun,
Benjamin Liou,
Zhengtao Chu,
Venette Fannin,
Rachel Blackwood,
Yanyan Peng,
Gregory A. Grabowski,
Harold W. Davis,
Xiaoyang Qi
Affiliations
Ying Sun
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Corresponding author at: Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, and Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Benjamin Liou
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Zhengtao Chu
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, College of Medicine, Cincinnati, OH, USA
Venette Fannin
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Rachel Blackwood
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Yanyan Peng
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Gregory A. Grabowski
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Harold W. Davis
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, College of Medicine, Cincinnati, OH, USA
Xiaoyang Qi
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, College of Medicine, Cincinnati, OH, USA; Corresponding author at: Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, and Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Background: Enzyme replacement therapy (ERT) can positively affect the visceral manifestations of lysosomal storage diseases (LSDs). However, the exclusion of the intravenous ERT agents from the central nervous system (CNS) prevents direct therapeutic effects. Methods: Using a neuronopathic Gaucher disease (nGD) mouse model, CNS-ERT was created using a systemic, non-invasive, and CNS-selective delivery system based on nanovesicles of saposin C (SapC) and dioleoylphosphatidylserine (DOPS) to deliver to CNS cells and tissues the corrective, functional acid β-glucosidase (GCase). Findings: Compared to free GCase, human GCase formulated with SapC-DOPS nanovesicles (SapC-DOPS-GCase) was more stable in serum, taken up into cells, mostly by a mannose receptor-independent pathway, and resulted in higher activity in GCase-deficient cells. In contrast to free GCase, SapC-DOPS-GCase nanovesicles penetrated through the blood-brain barrier into the CNS. The CNS targeting was mediated by surface phosphatidylserine (PS) of blood vessel and brain cells. Increased GCase activity and reduced GCase substrate levels were found in the CNS of SapC-DOPS-GCase-treated nGD mice, which showed profound improvement in brain inflammation and neurological phenotypes. Interpretation: This first-in-class CNS-ERT approach provides considerable promise of therapeutic benefits for neurodegenerative diseases. Funding: This study was supported by the National Institutes of Health grants R21NS 095047 to XQ and YS, R01NS 086134 and UH2NS092981 in part to YS; Cincinnati Children's Hospital Medical Center Research Innovation/Pilot award to YS and XQ; Gardner Neuroscience Institute/Neurobiology Research Center Pilot award to XQ and YS, Hematology-Oncology Programmatic Support from University of Cincinnati and New Drug State Key Project grant 009ZX09102-205 to XQ.
