Focused ultrasound increases gene delivery to deep brain structure following the administration of a recombinant adeno-associated virus in the cerebrospinal fluid

Gene delivery via adeno-associated viral vectors can provide lasting clinical benefits following a one-time treatment. Delivery throughout the brain is needed for the treatment of neurological disorders with widespread pathology, including Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis. Most gene vectors have poor diffusion in the brain tissue. Furthermore, it is only at high intravenous doses that gene vectors can overcome the blood-brain barrier. In contrast, relatively lower doses of gene vectors injected in the cerebrospinal fluid enable significant transduction of superficial brain regions. The remaining challenge and unmet need of gene therapy is to deliver gene vectors to deep brain structures using a minimally invasive strategy. Here, we demonstrate that non-invasive focused ultrasound blood-brain barrier modulation can increase the delivery of recombinant adeno-associated virus by 5-fold to deep brain structures following injection in the cisterna magna. Delivery of adeno-associated viral vectors to the central nervous system, via administration in the cerebrospinal fluid, is being evaluated in several clinical trials for treating beta-galactosidase-1 deficiency, Batten disease, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Our findings suggest that the efficacy of gene therapies delivered in the cerebrospinal fluid can be enhanced by targeting brain areas of interest with focused ultrasound. Significance statementAdministration of viral vectors in the cerebrospinal fluid through the cisterna magna is being evaluated in patients with neurological disorders. Focused ultrasound combined with intravenous microbubbles safely increases the permeability of the blood-brain barrier in humans and enables delivery of intravenous adeno-associated virus in non-human primates. Here, we demonstrate that combining these two clinically relevant gene delivery methods, intracisterna magna administration and focused ultrasound with microbubbles, can facilitate gene delivery to superficial and deep brain structures. Our findings have the potential to increase the efficacy of gene therapies, particularly for disorders with brain regions that have remained difficult to reach.