Kristiana Xhima1,2, Fadl Nabbouh3, Kullervo Hynynen1,4, Isabelle Aubert1,2, Anurag Tandon3,5. 1. Sunnybrook Research Institute, Toronto, Ontario, Canada. 2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 3. Tanz Centre for Research in Neurodegenerative Diseases, Toronto, Ontario, Canada. 4. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 5. Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND: The characteristic progression of Lewy pathology in Parkinson's disease likely involves intercellular exchange and the accumulation of misfolded α-synuclein amplified by a prion-like self-templating mechanism. Silencing of the α-synuclein gene could provide long-lasting disease-modifying benefits by reducing the requisite substrate for the spreading aggregation. OBJECTIVES: As a result of the poor penetration of viral vectors across the blood-brain barrier, gene therapy for central nervous system disorders requires direct injections into the affected brain regions, and invasiveness is further increased by the need for bilateral delivery to multiple brain regions. Here we test a noninvasive approach by combining low-intensity magnetic resonance-guided focused ultrasound and intravenous microbubbles that can transiently increase the access of brain impermeant therapeutic macromolecules to targeted brain regions. METHODS: Transgenic mice expressing human α-synuclein were subjected to magnetic resonance-guided focused ultrasound targeted to 4 brain regions (hippocampus, substantia nigra, olfactory bulb, and dorsal motor nucleus) in tandem with intravenous microbubbles and an adeno-associated virus serotype 9 vector bearing a short hairpin RNA sequence targeting the α-synuclein gene. RESULTS: One month following treatment, α-synuclein immunoreactivity was decreased in targeted brain regions, whereas other neuronal markers such as synaptophysin or tyrosine hydroxylase were unchanged, and cell death and glial activation remained at basal levels. CONCLUSIONS: These results demonstrate that magnetic resonance-guided focused ultrasound can effectively, noninvasively, and simultaneously deliver viral vectors targeting α-synuclein to multiple brain areas. Importantly, this approach may be useful to alter the progression of Lewy pathology along selected neuronal pathways, particularly as prodromal PD markers improve early diagnoses.
BACKGROUND: The characteristic progression of Lewy pathology in Parkinson's disease likely involves intercellular exchange and the accumulation of misfolded α-synuclein amplified by a prion-like self-templating mechanism. Silencing of the α-synuclein gene could provide long-lasting disease-modifying benefits by reducing the requisite substrate for the spreading aggregation. OBJECTIVES: As a result of the poor penetration of viral vectors across the blood-brain barrier, gene therapy for central nervous system disorders requires direct injections into the affected brain regions, and invasiveness is further increased by the need for bilateral delivery to multiple brain regions. Here we test a noninvasive approach by combining low-intensity magnetic resonance-guided focused ultrasound and intravenous microbubbles that can transiently increase the access of brain impermeant therapeutic macromolecules to targeted brain regions. METHODS:Transgenic mice expressing human α-synuclein were subjected to magnetic resonance-guided focused ultrasound targeted to 4 brain regions (hippocampus, substantia nigra, olfactory bulb, and dorsal motor nucleus) in tandem with intravenous microbubbles and an adeno-associated virus serotype 9 vector bearing a short hairpin RNA sequence targeting the α-synuclein gene. RESULTS: One month following treatment, α-synuclein immunoreactivity was decreased in targeted brain regions, whereas other neuronal markers such as synaptophysin or tyrosine hydroxylase were unchanged, and cell death and glial activation remained at basal levels. CONCLUSIONS: These results demonstrate that magnetic resonance-guided focused ultrasound can effectively, noninvasively, and simultaneously deliver viral vectors targeting α-synuclein to multiple brain areas. Importantly, this approach may be useful to alter the progression of Lewy pathology along selected neuronal pathways, particularly as prodromal PD markers improve early diagnoses.
Authors: Daniela Berg; Ronald B Postuma; Charles H Adler; Bastiaan R Bloem; Piu Chan; Bruno Dubois; Thomas Gasser; Christopher G Goetz; Glenda Halliday; Lawrence Joseph; Anthony E Lang; Inga Liepelt-Scarfone; Irene Litvan; Kenneth Marek; José Obeso; Wolfgang Oertel; C Warren Olanow; Werner Poewe; Matthew Stern; Günther Deuschl Journal: Mov Disord Date: 2015-10 Impact factor: 10.338
Authors: Manabu Kinoshita; Nathan McDannold; Ferenc A Jolesz; Kullervo Hynynen Journal: Proc Natl Acad Sci U S A Date: 2006-07-25 Impact factor: 11.205
Authors: 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; Richard J Price Journal: Nano Lett Date: 2017-05-18 Impact factor: 11.189
Authors: Kelvin C Luk; Cheng Song; Patrick O'Brien; Anna Stieber; Jonathan R Branch; Kurt R Brunden; John Q Trojanowski; Virginia M-Y Lee Journal: Proc Natl Acad Sci U S A Date: 2009-11-05 Impact factor: 11.205
Authors: María Izco; Javier Blesa; Martin Schleef; Marco Schmeer; Riccardo Porcari; Raya Al-Shawi; Stephan Ellmerich; María de Toro; Chris Gardiner; Yiqi Seow; Alejandro Reinares-Sebastian; Raquel Forcen; J Paul Simons; Vittorio Bellotti; J Mark Cooper; Lydia Alvarez-Erviti Journal: Mol Ther Date: 2019-08-27 Impact factor: 11.454
Authors: Klazina Kooiman; Silke Roovers; Simone A G Langeveld; Robert T Kleven; Heleen Dewitte; Meaghan A O'Reilly; Jean-Michel Escoffre; Ayache Bouakaz; Martin D Verweij; Kullervo Hynynen; Ine Lentacker; Eleanor Stride; Christy K Holland Journal: Ultrasound Med Biol Date: 2020-03-10 Impact factor: 2.998
Authors: Colleen T Curley; Brian P Mead; Karina Negron; Namho Kim; William J Garrison; G Wilson Miller; Kathryn M Kingsmore; E Andrew Thim; Ji Song; Jennifer M Munson; Alexander L Klibanov; Jung Soo Suk; Justin Hanes; Richard J Price Journal: Sci Adv Date: 2020-05-01 Impact factor: 14.136
Authors: Wisberty J Gordián-Vélez; Dimple Chouhan; Rodrigo A España; H Isaac Chen; Jason A Burdick; John E Duda; D Kacy Cullen Journal: Brain Res Bull Date: 2021-07-28 Impact factor: 3.715