Parkinson’s disease damages dopamine neurons in the part of the brain called the substantia nigra (SN). Scientists hypothesize that these damaged cells can be repaired, and previous studies found that DNA segments that were introduced through the intranasal route of administration could produce a dopamine cell survival factor called glial cell derived neurotrophic factor (GDNF) that protected these cells in the SN. Researchers at Northeastern University, Brigham and Women’s Hospital, and Copernicus Therapeutics conducted a study to use focused ultrasound and microbubbles to improve on this concept.
Barbara Waszczak, PhD, is a neuroscientist at Northeastern University in Boston who is pioneering the use of GDNF to repair damaged neurons in a rat model of Parkinson’s disease. “If given early in the disease, it is widely believed that GDNF could arrest Parkinson’s progression and promote the recovery and regeneration of the surviving dopamine neurons,” she says on her laboratory website. The GDNF is produced in the brain by DNA nanoparticles, and she administers them through a non-invasive method: intranasally. Dr. Waszczak has been working with Mark Cooper, MD, at Copernicus Therapeutics, Inc., who engineered the technology that encapsulates and compacts the GDNF DNA into nanoparticles for administration.
Nathan McDannold, PhD, is a focused ultrasound drug delivery expert who is also in Boston – at Brigham and Women’s Hospital. Drs. Waszczak and McDannold met at the September 2013 Focused Ultrasound Foundation Mini Brain Workshop on the Blood Brain Barrier and Targeted Drug Delivery, where they learned of each other’s work and hatched this collaboration.
Together the team set out to investigate whether focused ultrasound could increase DNA nanoparticle delivery to the brain after intranasal administration. They proposed that an increase in total DNA delivery due to the application of focused ultrasound would result in increased transfection and transgene expression in the sonicated regions of the rat brain. If successful, this would support development of a combined focused ultrasound plus intranasal administration option as a non-invasive means of gene therapy for Parkinson’s disease, and possibly other neurodegenerative disorders of the brain.
The first part of the project examined different energy parameters and treatment conditions to determine whether focused ultrasound could increase total plasmid DNA nanoparticle delivery and transgene expression in the sonicated regions: the substantia nigra and striatum. They found that focused ultrasound and microbubbles had a similar effect in enhancing transgene expression regardless of whether it was applied before or after intranasal administration.
Next, the team tested whether focused ultrasound would improve tissue penetration and alter cellular transfection patterns in the sonicated regions. If successful, focused ultrasound could be the key to enabling agents with poor capabilities for crossing the blood-brain barrier (BBB) to become disease-altering therapies. They found that focused ultrasound did increase transgene expression at the sonication site one week after intranasal administration of the nanoparticles. However, it did not shift the distribution of cellular transfection from pericytes to neurons or astrocytes; instead, it appeared to increase transfection of another cell type, possibly microglia, at the sonication sites.
Overall, focused ultrasound plus microbubbles enhanced transgene expression and improved tissue penetration in the targeted brain regions. “This work provides new insights and additional questions regarding the feasibility of focused ultrasound for increasing intranasal delivery to the brain,” said Dr. Waszczak. “Moving forward, we hope to refine the focused ultrasound protocols, address the new questions, and further explore this approach for treating Parkinson’s and other central nervous system disorders.” To further this research, the team is planning to submit an NIH proposal.