Gene Therapy for Parkinson’s Disease: Towards Non Invasive Approaches

Abstract

The blood brain barrier (BBB) is one of the factors hampering the development of new therapies and in many cases limits the access of the therapeutic agent to the neural tissue. The BBB consists of a specialized vascular structure formed by the interaction between endothelial cells and numerous processes of astrocytes regulating the passage and diffusion of molecules between plasma and the central nervous system (CNS) (Pardridge, 2005). The endothelium is distinguished from other tissues by the presence of tight junctions between endothelial cells (which limit the exchange of even low molecular weight substances) and a reduced endocytic and pinocytic activity. Small molecules (usually less than 500 Da) and some lipid-soluble small peptides can pass the BBB without the mediation of specific transporters. However, in most cases, the transfer across the BBB requires receptor-mediated transcytosis or selective transporters, such as low density lipoprotein receptors (LDLR), insulin receptors, leptin receptors, transferrin receptors and insulin-like growth factor receptors (Pardridge, 2005). The number of specific transporters mediating the transfer of substances through the BBB is very high and probably accounts for a very substantial part of the more than 2,000 membrane transporters that probably function in the human cell. We present, in this review, some of the newly developed approaches to overcome this barrier and facilitate the access of therapeutic genes to the nervous system. Parkinson's disease (PD) is considered here as being neurological diseases for which no etiopathogenic treatment is available and may be susceptible to gene therapy. Different proteins such as human glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF)...which are able to reduce the vulnerability of dopaminergic neurons in laboratory animals have been described in the last ten years. For various reasons, the central administration of these proteins has not been effective in patients (short half-life, poor diffusion in neural tissue ...). Since the cellular and neurochemical substrate of the disease, and various proteins with neuroprotective capacity for these cells are known, gene therapy is outlined here as a future therapeutic option.