Systemic enzyme delivery by blood-brain barrier-penetrating SapC-DOPS nanovesicles for treatment of neuronopathic Gaucher disease

Abstract

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 b-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.

Reuse of Molecules for Glioblastoma Therapy

“…Neoplastic cells are predicted to be sensitive to cytotoxicity of the saposin-fat complexes. As a membrane-associated protein, SapC can tightly bind the negatively charged phospholipids (DOPS) to form a stable and pharmacologic active nanovesicle, SapC-DOPS [ 115 , 116 ]. This “nanodrug” selectively targets phosphatidylserine, a surface lipid biomarker on tumor cells and vessels [ 117 , 118 ].…”

“…Tumor-specific cytotoxicity of SapC-DOPS on a variety of cancer types leads to apoptotic and lysosomal cell death, thus inhibiting tumor growth and improving survival of tumor-bearing animals [ 119 , 120 ]. SapC-DOPS has been previously studied in pancreatic, lung, pediatric, and other brain tumors [ 116 ]. As for suggesting its use in the GBM space, SapC-DOPS penetrates the BBB and BTB to regress brain tumors in mice [ 116 , 121 ].…”

“…SapC-DOPS has been previously studied in pancreatic, lung, pediatric, and other brain tumors [ 116 ]. As for suggesting its use in the GBM space, SapC-DOPS penetrates the BBB and BTB to regress brain tumors in mice [ 116 , 121 ]. In addition, SapC-DOPS technology may potentially find use as a carrier of imaging agents to a tumor [ 114 , 122 , 123 ].…”

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

“…SapC-DOPS-GCase-containing nanovesicles were able to penetrate through BBB via the surface phosphatidylserine. These vesicles also led to a reduction of GCase substrate levels, attenuating brain inflammation (Sun et al, 2020 ).…”

Biotherapy of Brain Tumors with Phosphatidylserine-Targeted Radioiodinated SapC-DOPS Nanovesicles

“…A synergistic effect of SapC-DOPS and TMZ has been demonstrated for GBM in mice [ 31 ]. In addition, we have recently demonstrated that SapC-DOPS can cross the BBB to deliver a deficient enzyme and effectively treat a mouse model of Gaucher disease [ 32 ]. Importantly, we have recently demonstrated that radiation increases surface PS on a variety of cancer cells and that this enhances the killing of the cells by SapC-DOPS both in vitro and in subcutaneous tumors in a combination therapeutic approach [ 33 ].…”