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. 2017 Jun 14;17(6):3533-3542.
doi: 10.1021/acs.nanolett.7b00616. Epub 2017 May 18.

Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model

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Free PMC article

Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model

Brian P Mead et al. Nano Lett. .
Free PMC article

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; Parkinson’s disease; blood−brain barrier; nonviral gene delivery.

Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
MR imaging for guidance, confirmation, and safety evaluation of FUS treatments. (A) The treatment site (i.e., 6-OHDA lesioned striatum) was targeted with T2 pre-FUS images. (C) BBB opening in the striatum was confirmed with post-FUS contrast-enhanced T1 imaging. (B, D) Treatment safety was assessed by comparing pre- and post-FUS T2* images. Hypointensities in T2* images, indicating red-blood cell accumulation, were never observed in FUS-treated animals (n = 32).
Figure 2
Figure 2
FUS-mediated delivery of GDNF-BPN to the striatum of PD rats leads to a significant increase in GDNF protein levels in the striatum. Bar graphs show GDNF protein levels in the ipsilateral (black) and contralateral (gray) striatum. n = 5 (6-OHDA + FUS + GDNF-BPN), n = 4 or n = 3 (6-OHDA + GDNF-BPN) in each group at each time point. *Significantly different from all groups at the same time point (p < 0.05).
Figure 3
Figure 3
FUS-mediated delivery of GDNF-BPN improves dopamine levels in the ipsilateral hemisphere. Bar graph of dopamine levels in the striatum in the ipsilateral (black) and contralateral (gray) hemisphere at weeks 2, 6, or 12 after 6-OHDA administration. n = 5 (6-OHDA + FUS + GDNF-BPN), n = 4 (6-OHDA only), or n = 3 in each group at each time point. *p < 0.05 vs all groups at the same time point and same hemisphere. **p < 0.05. +p < 0.05 vs contralateral at same time point.
Figure 4
Figure 4
Delivery of GDNF-BPN to the striatum with FUS increases dopaminergic neuron density in the striatum and SNpc. Representative images of TH-stained coronal sections through the striatum (A) or SNpc (B) at either week 6 (top row) or week 12 (bottom row) after 6-OHDA administration. Bar graphs show inverse TH staining intensity (C) or TH+ cell number (D) normalized to contralateral. n = 5 (6-OHDA + FUS + GDNF-BPN) or n = 4 in each group and time point. *p, 0.05 vs all groups at same time point.
Figure 5
Figure 5
Delivery of GDNF-BPN with FUS restores locomotor function in PD rats. (A) Line graph of average contralateral rotations per minute after apomorphine administration. (B) Line graph of contralateral touch fraction in the forepaw use bias test. n > 14 in each group at weeks 0 through 6; n > 7 in each group at weeks 8 through 12. *Significantly different than all other groups at the same time point (p < 0.01).

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