title: Highly PEGylated DNA Nanoparticles Provide Uniform and Widespread Gene Transfer in the Brain.
abstract: Gene delivery to the central nervous system (CNS) has potential as a means for treating numerous debilitating neurological diseases. Nonviral gene vector platforms are tailorable and can overcome key limitations intrinsic to virus-mediated delivery; however, lack of clinical efficacy with nonviral systems to date may be attributed to limited gene vector dispersion and transfection in vivo. It is shown that the brain extracellular matrix (ECM) strongly limits penetration of polymer-based gene vector nanoparticles (NP) through the brain parenchyma, even when they are very small (<60 nm) and coated with a polyethylene glycol (PEG) corona of typical density. Following convection enhanced delivery (CED), conventional gene vectors are confined to the injection site, presumably by adhesive interactions with the brain ECM and do not provide gene expression beyond the point of administration. In contrast, it is found that incorporating highly PEGylated polymers allows the production of compacted (≈43 nm) and colloidally stable DNA NP that avoid adhesive trapping within the brain parenchyma. When administered by CED into the rat striatum, highly PEGylated DNA NP distribute throughout and provide broad transgene expression without vector-induced toxicity. The use of these brain-penetrating gene vectors, in conjunction with CED, offers an avenue to improve gene therapy for CNS diseases.
authors.affiliation: Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21231, USA.|Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21297, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mastorakos
authors.affiliation: Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21231, USA.|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.
authors.forename: Clark
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21231, USA.|Center for Biotechnology Education, Krieger School of Arts and Sciences, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD, 21218, USA.
authors.forename: Sneha
authors.initials: S
authors.lastname: Berry
authors.affiliation: Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21231, USA.|Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 601 N. Caroline Street, Baltimore, MD, 21287, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21231, USA.|Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 601 N. Caroline Street, Baltimore, MD, 21287, USA.
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.affiliation: Departments of Neurological Surgery Anatomy and Neurobiology, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD, 21201, USA.
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Woodworth
authors.affiliation: Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21231, USA.|Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21297, USA.
authors.forename: Jung Soo
authors.initials: JS
authors.lastname: Suk
authors.affiliation: Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21231, USA.|Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21297, USA.|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA.|Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD, 21218, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics*; D005109:Extracellular Matrix / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D053758:Nanoparticles / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011108:Polymers / Q000008:administration & dosage; D011817:Rabbits; D051381:Rats; D014162:Transfection / Q000379:methods; D019076:Transgenes / Q000235:genetics
chemical_list: D011108:Polymers; D011092:Polyethylene Glycols; D004247:DNA
keywords: brain tissue barrier; central nervous system diseases; convection enhanced delivery; extracellular matrix; nonviral gene therapy