Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes
Open Access
- 7 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 10 (1), 1-12
- https://doi.org/10.1038/s41598-020-70290-w
Abstract
Niemann-Pick C1 (NPC1) is a lysosomal cholesterol storage disorder, that severely affects the brain, and is caused by mutations in the NPC1 gene, which encodes an intracellular membrane transporter of non-esterified cholesterol. Therapeutic options for NPC1 are few, and classical enzyme replacement therapy with the recombinant protein is not possible as the NPC1 gene product is an insoluble membrane protein, which increases the need for development of gene therapy for NPC1. While viral based gene therapy is under development, it is important to investigate alternative approaches to brain gene therapy without viral vectors. The present work develops a plasmid DNA approach to gene therapy of NPC1 using Trojan horse liposomes (THLs), wherein the plasmid DNA is encapsulated in 100 nm pegylated liposomes, which are targeted to organs with a monoclonal antibody against the mouse transferrin receptor. THLs were encapsulated with a 8.0 kb plasmid DNA encoding the 3.9 kb human NPC1 open reading frame, under the influence of a 1.5 kb platelet derived growth factor B (PDGFB) promoter. THLs were administered weekly beginning at 6-7 weeks in the NPC1(-/-) null mouse, and delivery of the plasmid DNA, and NPC1 mRNA expression in brain, spleen, and liver were confirmed by quantitative PCR. THL treatment reduced tissue inclusion bodies in brain, and peripheral organs, but did not prolong lifespan in these mice. The work suggests that early treatment after birth may be required to reverse this disease model with NPC1 gene replacement therapy.Funding Information
- National Institute of Neurological Disorders and Stroke (R44NS098877)
This publication has 42 references indexed in Scilit:
- Preclinical Differences of Intravascular AAV9 Delivery to Neurons and Glia: A Comparative Study of Adult Mice and Nonhuman PrimatesMolecular Therapy, 2011
- Weekly Cyclodextrin Administration Normalizes Cholesterol Metabolism in Nearly Every Organ of the Niemann-Pick Type C1 Mouse and Markedly Prolongs LifePediatric Research, 2010
- Iron uptake from plasma transferrin by a transferrin receptor 2 mutant mouse model of haemochromatosisJournal of Hepatology, 2010
- Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytesNature Biotechnology, 2008
- Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood–brain barrier delivery in the mouseBiotechnology & Bioengineering, 2008
- Development, Validation, and Clinical Implementation of an Assay to Measure Total Antibody Response to Naglazyme® (Galsulfase)The AAPS Journal, 2008
- Cholesterol Accumulation Is Associated with Lysosomal Dysfunction and Autophagic Stress in Npc1−/− Mouse BrainThe American Journal of Pathology, 2007
- Comparison of cDNA and genomic forms of tyrosine hydroxylase gene therapy of the brain with Trojan horse liposomesThe Journal of Gene Medicine, 2007
- Platelet-derived growth factor expression in a transgenic modelKidney International, 1992
- A lysosomal storage disorder in mice characterized by a dual deficiency of sphingomyelinase and glucocerebrosidaseBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1980