한빛사논문
- 조회1,869
Brian P. Mead,† Namho Kim,‡ G. Wilson Miller,†,§ David Hodges,† Panagiotis Mastorakos,‡ Alexander L. Klibanov,†,⊥ James W. Mandell,# Jay Hirsh,∇ Jung Soo Suk,*,‡ Justin Hanes,*,‡ and Richard J. Price*,†
†Department of Biomedical Engineering, §Department of Radiology and Medical Imaging, ⊥Cardiovascular Division, #Department of Pathology, ∇Department of Biology, University of Virginia, Charlottesville, Virginia 22908, United States ‡Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States
*Corresponding Authors
Abstract
Therapies capable of decelerating, or perhaps even halting, neurodegeneration in Parkinson’s disease (PD) remain elusive. Clinical trials of PD gene therapy testing the delivery of neurotrophic factors, such as the glial cell-line derived neurotrophic factor (GDNF), have been largely ineffective due to poor vector distribution throughout the diseased regions in the brain. In addition, current delivery strategies involve invasive procedures that obviate the inclusion of early stage patients who are most likely to benefit from GDNF-based gene therapy. Here, we introduce a two-pronged treatment strategy, composed of MR image-guided focused ultrasound (FUS) and brain-penetrating nanoparticles (BPN), that provides widespread but targeted GDNF transgene expression in the brain following systemic administration. MR image-guided FUS allows circulating gene vectors to partition into the brain tissue by noninvasive and transient opening of the blood–brain barrier (BBB) within the areas where FUS is applied. Once beyond the BBB, BPN provide widespread and uniform GDNF expression throughout the targeted brain tissue. After only a single treatment, our strategy led to therapeutically relevant levels of GDNF protein content in the FUS-targeted regions in the striatum of the 6-OHDA-induced rat model of PD, which lasted at least up to 10 weeks. Importantly, our strategy restored both dopamine levels and dopaminergic neuron density and reversed behavioral indicators of PD-associated motor dysfunction with no evidence of local or systemic toxicity. Our combinatorial approach overcomes limitations of current delivery strategies, thereby potentially providing a novel means to treat PD.
KEYWORDS: Focused ultrasound, nonviral gene delivery, Parkinson’s disease, blood−brain barrier
논문정보
- Research article
- 2017년 05월 (BRIC 등록일 2019-06-21)
- 국외 연구진
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
