Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound

被引:116
作者
Mead, Brian P. [1 ]
Mastorakos, Panagiotis [2 ,3 ]
Suk, Jung Soo [2 ]
Klibanov, Alexander L. [1 ,4 ]
Hanes, Justin [2 ]
Price, Richard J. [1 ]
机构
[1] Univ Virginia, Biomed Engn, Charlottesville, VA 22908 USA
[2] Johns Hopkins Univ, Sch Med, Ctr Nanomed, Wilmer Eye Inst, Baltimore, MD 21231 USA
[3] Univ Virginia, Dept Neurol Surg, Charlottesville, VA 22908 USA
[4] Univ Virginia, Cardiovasc Div, Charlottesville, VA 22908 USA
关键词
Focused ultrasound; Non-viral gene delivery; CNS diseases; Blood-brain barrier; PARKINSONS-DISEASE; BARRIER DISRUPTION; RAT-BRAIN; NIGROSTRIATAL PATHWAY; ALZHEIMERS-DISEASE; ENHANCED DELIVERY; SKELETAL-MUSCLE; NUCLEIC-ACIDS; AMYLOID-BETA; MOUSE MODEL;
D O I
10.1016/j.jconrel.2015.12.034
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Gene therapy holds promise for the treatment of many pathologies of the central nervous system (CNS), including brain tumors and neurodegenerative diseases. However, the delivery of systemically administered gene carriers to the CNS is hindered by both the blood-brain barrier (BBB) and the nanoporous and electrostatically charged brain extracelluar matrix (ECM), which acts as a steric and adhesive barrier. We have previously shown that these physiological barriers may be overcome by, respectively, opening the BBB with MR image-guided focused ultrasound (FUS) and microbubbles and using highly compact "brain penetrating" nanoparticles (BPN) coated with a dense polyethylene glycol corona that prevents adhesion to ECM components. Here, we tested whether this combined approach could be utilized to deliver systemically administered DNA-bearing BPN (DNA-BPN) across the BBB and mediate localized, robust, and sustained transgene expression in the rat brain. Systemically administered DNA-BPN delivered through the BBB with FUS led to dose-dependent transgene expression only in the FUS-treated region that was evident as early as 24 h post administration and lasted for at least 28 days. In the FUS-treated region similar to 42% of all cells, including neurons and astrocytes, were transfected, while less than 6% were transfected in the contralateral non-FUS treated hemisphere. Importantly, this was achieved without any sign of toxicity or astrocyte activation. We conclude that the image-guided delivery of DNA-BPN with FUS and microbubbles constitutes a safe and non-invasive strategy for targeted gene therapy to the brain. (C) 2015 Elsevier B.V. All rights reserved.
引用
收藏
页码:109 / 117
页数:9
相关论文
共 70 条
[1]   GDNF, NGF and BDNF as therapeutic options for neurodegeneration [J].
Allen, Shelley J. ;
Watson, Judy J. ;
Shoemark, Deborah K. ;
Barua, Neil U. ;
Patel, Nikunj K. .
PHARMACOLOGY & THERAPEUTICS, 2013, 138 (02) :155-175
[2]   Focal Delivery of AAV2/1-transgenes Into the Rat Brain by Localized Ultrasound-induced BBB Opening [J].
Alonso, Angelika ;
Reinz, Eileen ;
Leuchs, Barbara ;
Kleinschmidt, Juergen ;
Fatar, Marc ;
Geers, Bart ;
Lentacker, Ine ;
Hennerici, Michael G. ;
de Smedt, Stefaan C. ;
Meairs, Stephen .
MOLECULAR THERAPY-NUCLEIC ACIDS, 2013, 2 :e73
[3]   Gene therapy with AAV2-CDNF provides functional benefits in a rat model of Parkinson's disease [J].
Back, Susanne ;
Peranen, Johan ;
Galli, Emilia ;
Pulkkila, Paivi ;
Lonka-Nevalaita, Liina ;
Tamminen, Tuulia ;
Voutilainen, Merja H. ;
Raasmaja, Atso ;
Saarma, Mart ;
Mannisto, Pekka T. ;
Tuominen, Raimo K. .
BRAIN AND BEHAVIOR, 2013, 3 (02) :75-88
[4]   Nonviral approaches for neuronal delivery of nucleic acids [J].
Bergen, Jamie M. ;
Park, In-Kyu ;
Horner, Philip J. ;
Pun, Suzie H. .
PHARMACEUTICAL RESEARCH, 2008, 25 (05) :983-998
[5]  
Berry M, 2001, CURR OPIN MOL THER, V3, P338
[6]   Gene Therapy for Parkinson's Disease [J].
Bjorklund, Tomas ;
Kordower, Jeffrey H. .
MOVEMENT DISORDERS, 2010, 25 (03) :S161-S173
[7]   CONVECTION-ENHANCED DELIVERY OF MACROMOLECULES IN THE BRAIN [J].
BOBO, RH ;
LASKE, DW ;
AKBASAK, A ;
MORRISON, PF ;
DEDRICK, RL ;
OLDFIELD, EH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (06) :2076-2080
[8]   Highly compacted DNA nanoparticles with low MW PEG coatings: In vitro, ex vivo and in vivo evaluation [J].
Boylan, Nicholas J. ;
Suk, Jung Soo ;
Lai, Samuel K. ;
Jelinek, Raz ;
Boyle, Michael P. ;
Cooper, Mark J. ;
Hanes, Justin .
JOURNAL OF CONTROLLED RELEASE, 2012, 157 (01) :72-79
[9]   Targeted Delivery of Neural Stem Cells to the Brain Using MRI-Guided Focused Ultrasound to Disrupt the Blood-Brain Barrier [J].
Burgess, Alison ;
Ayala-Grosso, Carlos A. ;
Ganguly, Milan ;
Jordao, Jessica F. ;
Aubert, Isabelle ;
Hynynen, Kullervo .
PLOS ONE, 2011, 6 (11)
[10]   Ultrasound-activated Agents Comprised of 5FU-bearing Nanoparticles Bonded to Microbubbles Inhibit Solid Tumor Growth and Improve Survival [J].
Burke, Caitlin W. ;
Alexander, Eben ;
Timbie, Kelsie ;
Kilbanov, Alexander L. ;
Price, Richard J. .
MOLECULAR THERAPY, 2014, 22 (02) :321-328