R.G. Goya, J.I. Schwerdt, O. Mykhaylyk, M.B. Casalini, B. Poch, R.B. Correia

Insulin-like growth factor I (IGF-I) is a powerful neurotrophic molecule which appears to be part of the physiologic self-repair mechanisms of the adult brain. Using the aging female rat as a model of age-related dopaminergic (DA) neurodegeneration, we have implemented short-term restorative IGF-I gene therapy in the hypothalamus and cerebral ventricles. Short-term (17 days) intrahypothalamic IGF-I gene therapy achieved a nearly full restoration of hypothalamic DA neuron function as determined by morphometric analysis and by correction of the chronic hyperprolactinemia that typically develops in senescent (28-30 mo.) female rats as a consequence of hypothalamic DA neuron dysfunction. Short-term intracerebroventricular (ICV) IGF-I gene therapy was able to ameliorate motor performance in senescent females which typically show a marked decline in motor function as compared to young (2 mo.) counterparts. Although our and others’ studies reveal that IGF-I has a high restorative potential in the aging brain, up to now the only way to administer the therapeutic vectors is via stereotaxic injections in the target brain areas. The invasiveness of this procedure significantly limits its eventual implementation in human patients. The association of viral vector-based gene delivery with nanotechnology now offers the possibility of developing minimally invasive gene therapy strategies for the brain. This approach combines Magnetic Drug Targeting (MDT) and magnetofection, two novel methodologies based on the use of magnetic nanoparticles (MNP). The goal of MDT is to concentrate magnetically responsive therapeutic complexes in target areas of the body by means of external magnetic fields. Magnetofection is a methodology developed in the early 2000’s by Christian Plank’s group, in Munich, Germany. It is based on the association of MNP with nonviral or viral vectors in order to optimize gene delivery in the presence of a magnetic field. Thus, the German group could develop magnetic nanoparticle formulations that improve considerably the efficiency of adenovirally-mediated gene delivery. Based on the capabilities of the above technologies we have undertaken to develop, in collaboration with the German team, minimally invasive IGF-I gene delivery to the brain. This will be achieved by ICV administration of MNP-viral vector complexes at distal sites and magnetic trapping of the complexes at the target brain region by means of a properly focused external magnetic field. The progress of these studies will be discussed. The long-term goal of our endeavor is to use this technology to implement minimally invasive gene therapy in Alzheimer and Parkinson patients as well as in other neurological pathologies amenable to gene therapy intervention.

Keywords (Optional): 
Brain aging
Gene therapy
Magnetic nanoparticles