MRI-guided focused ultrasound for treating Parkinson's disease with human mesenchymal stem cells.
Authors: Wu SK, Tsai CL, Mir A, Hynynen K
Parkinson's disease (PD) is a progressive disorder that affects the nervous system and causes regions of the brain to deteriorate. In this study, we investigated the effects of MR-guided focused ultrasound (MRgFUS) for the delivery of human mesenchymal stem cells (MSCs) on the 6-hydroxydopamine (6-HODA)-induced PD rat model. MRgFUS-induced blood-brain barrier (BBB) permeability modulation was conducted using an acoustic controller with the targets at the striatum (ST) and SN. Human MSCs were injected immediately before sonication. Here, we show that we can deliver human MSCs into Parkinsonian rats through MRgFUS-induced BBB modulation using an acoustic controller. Stem cells were identified in the sonicated brain regions using surface markers, indicating the feasibility of MSC delivery via MRgFUS. MSCs + FUS treatment significantly improved the behavioural outcomes compared with control, FUS alone, and MSCs alone groups (p < 0.05). In the quantification analysis of the TH stain, a significant reservation of dopamine neurons was seen in the MSCs + FUS group as compared with the MSCs group (ST: p = 0.03; SN: p = 0.0005). Mesenchymal stem cell therapy may be a viable treatment option for neurodegenerative diseases such as Parkinson's. Transcranial MRgFUS serves as an efficacious and safe method for targeted and minimally invasive stem cell homing.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To evaluate whether transcranial MR-guided focused ultrasound enhances targeted delivery and therapeutic efficacy of human bone marrow-derived mesenchymal stem cells in a 6-OHDA rat model of Parkinson’s disease compared with intravenous MSC administration.
Animal model / Human subject
Rattus norvegicus (Wistar strain); age not reported; male; mean weight 301 ± 11 g
Disease model
Parkinson's disease (6-hydroxydopamine-induced rat model)
MRI or image guidance method
MR-guided focused ultrasound (MRgFUS) with an acoustic controller targeting the striatum (ST) and substantia nigra (SN)
Targeted brain region(s)
Striatum
Cargo name and characteristics
Human mesenchymal stem cells (MSCs) — human-derived multipotent stromal/stem cell therapy, delivered (injected immediately before sonication) for targeted homing to striatum and substantia nigra; identified by surface markers; used to preserve dopaminergic neurons in 6-hydroxydopamine PD rat model.
Outcomes and Safety
Summary of Outcomes
MRgFUS-mediated BBB opening enabled delivery of human MSCs into the striatum and substantia nigra, producing significant behavioral improvement and preservation of TH+ dopaminergic neurons (ST p=0.03; SN p=0.0005) with no acute hemorrhage, using 10 ms pulses at 1 Hz with Definity microbubbles (20 µL/kg) and controller-guided pressures that achieved BBB-opening thresholds of ~0.40–0.42 MPa (baseline emissions recorded at 0.128 MPa).
Duration of biological effect
2 h
Safety-related matter
The treatment was well tolerated with no evidence of acute hemorrhage, MRI- or histology-detected tissue damage, or abnormal behaviour in treated animals, supporting MRgFUS as a safe delivery method. The authors caution that FUS bioeffects require careful monitoring to avoid overexposure, and note potential adverse issues with alternative BBB opening (mannitol may cause vaso-vagal responses and focal seizures) and with long-term immunosuppression, which can produce several side effects.
Brain Region
Ultrasound Parameters
Focal Characteristics
Focal depth: None; Focal length: None; Aperture size: None
Treatment frequency
single session
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