TY - JOUR
T1 - Highly PEGylated DNA Nanoparticles Provide Uniform and Widespread Gene Transfer in the Brain
AU - Mastorakos, Panagiotis
AU - Zhang, Clark
AU - Berry, Sneha
AU - Oh, Yumin
AU - Lee, Seulki
AU - Eberhart, Charles G.
AU - Woodworth, Graeme F.
AU - Suk, Jung Soo
AU - Hanes, Justin
N1 - Publisher Copyright:
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
KW - Brain tissue barrier
KW - Central nervous system diseases
KW - Convection enhanced delivery
KW - Extracellular matrix
KW - Nonviral gene therapy
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U2 - 10.1002/adhm.201400800
DO - 10.1002/adhm.201400800
M3 - Article
C2 - 25761435
AN - SCOPUS:84929515431
SN - 2192-2640
VL - 4
SP - 1023
EP - 1033
JO - Advanced Healthcare Materials
JF - Advanced Healthcare Materials
IS - 7
ER -