José Luis Lanciego
Senior Researcher of the Gene Therapy in Neurodegenerative Diseases Programme at the Centre for Applied Medical Research (CIMA), University of Navarra
A Spanish-Japanese international team led by researchers from the Centro Integral de Neurociencias Abarca Campal (Hospital Universitario HM Puerta del Sur, Móstoles, Madrid), has managed to transiently permeabilise the blood-brain barrier (BBB) in non-human primates and Parkinsonian patients using a technique known as Low Intensity Focused Ultrasound (LIFU). In this way, they have achieved that an adeno-associated viral vector (AAV), administered systemically, crosses this barrier only in a specific area of interest and thus transfects brain neurons through a minimally invasive and safe procedure, opening the door to its application in patients, even in the short term.
The composition of the BBB isolates the brain from the peripheral circulation and limits the penetration of therapeutic agents, which is a major problem when designing new treatments for neurodegenerative diseases in general, and Parkinson's disease in particular. Any new treatment must fulfil three premises, as follows: (1) it must be able to cross the BBB, (2) it must reach the target area of interest and not be distributed homogeneously throughout the brain, in order to avoid adverse effects, and (3) once at the given target, the concentration of the product must be high enough to be effective.
Gene therapy uses AAV-like viral vectors as Trojan horses that have been modified in the laboratory to carry a gene of interest, which when expressed in neurons in the target area causes the cells to produce a specific therapeutic protein encoded by the gene. To date, all ongoing clinical trials with gene therapy products use the intraparenchymal route, whereby the target area is reached using stereotactic neurosurgical procedures, obviously an invasive option.
The main advantage of the LIFU technique described in this article is that it temporarily opens the BBB only in the area of interest, so that a systemically administered AAV vector can access the neurons located in the target area (in the putamen nucleus, in the case of this article) and transfect them specifically to express a specific therapeutic protein. In this way, the interior of the brain parenchyma is reached in a minimally invasive way that does not require neurosurgical procedures and is safe and effective, which, taken as a whole, represents a major advance in research into new therapies for Parkinson's disease.