Nathalie Vacaresse, Canada
Sunnybrook Research Institute Biological SciencesAuthor Of 1 Presentation
FOCUSED ULTRASOUND MEDIATES NON-INVASIVE GENE DELIVERY TO BRAIN AREAS RELEVANT TO ALZHEIMER’S AND PARKINSON’S DISEASES
Abstract
Aims
We aim to develop a gene therapy platform for the non-invasive delivery of transgenes efficiently targeting pathologies in brain areas affected by Alzheimer’s and Parkinson’s diseases. Therapies based on recombinant proteins, such as antibodies, have shown promises for the treatment of neurodegenerative disorders. To overcome the blood-brain barrier, current delivery strategies require repeated injections of proteins at high dosage. Gene therapy holds the potential of a one-time administration, resulting in the long-term expression of recombinant proteins for sustained therapeutic effects. The safe, low-dose, and non-invasive delivery to the brain of a gene carrier, such as adeno-associated virus (AAV), still represents an unmet need in the field of gene therapy.
Methods
We use focused ultrasound and intravenously injected microbubbles to temporarily increase the permeability of the blood-brain barrier and deliver intravenous AAVs non-invasively to the brain.
Results
AAVs of different serotypes were delivered to the hippocampus, cortex, striatum and other brain regions relevant to neurodegenerative disorders. We established the impact of ultrasound parameters, promoters, and AAV capsids on AAV delivery to specific cell types, to restricted–or to large and diffuse–brain areas.
Conclusions
This systematic and thorough investigation of the use of focused ultrasound and microbubbles for delivery of intravenous AAVs to the brain provides the foundation of a gene therapy platform. This approach can be tailored for cell-type specificity and the required volume of brain area(s) to be treated, thereby enabling efficient delivery of therapeutic genes were they are most needed in cases of Alzheimer’s and Parkinson’s diseases.