In vivo gene therapy as a potential treatment for Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects 1 percent of the population above the age of 60. While relatively rare genetic forms exist (Mouradian, 2002), its cause in the vast majority of sporadic cases remains to be established. The cardinal features of PD (bradykinesia, resting tremor, and rigidity) result from a loss of striatal dopamine secondary to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SN). Motor dysfunction worsens and additional incapacitating features such as dementia and depression can appear as the disease progresses (see Chapter 3). After decades of research, levodopa remains the most potent antiparkinsonian treatment. However, virtually all patients will ultimately suffer from disabling dyskinesia and wearing-off effects, making the use of levodopa as well as dopaminergic agonists, problematic. It is essential that novel therapeutic strategies be designed to provide potent long-term benefit without disabling side effects for these patients. Gene delivery systems are ideal for delivering therapeutic molecules to specific regions of the CNS. Via gene therapy, a piece or pieces of DNA placed into a carrying vector encoding for a substance of interest can be introduced into cells. Gene therapy can be applied ex vivo (genetically modifying cells in culture and then grafting those cells) or in vivo (genetically modifying host cells). In vivo gene therapy is when a vector carrying a gene of interest is introduced directly into the brain and not through a cell mediator. The vectors most commonly used are viral-derived such as adenovirus (AV), adenoassociated virus (AAV), lentivirus (LV), and herpes simplex virus (HSV). An ideal vector should have (1) high concentration, allowing many cells to be infected, (2) easy and reproducible production, (3) the ability to integrate in a site specific location in the host chromosome, or to be successfully maintained as a stable episome, and (4) lack of components that could elicit an immune response. Such vectors are currently available (Bensadoun et al., 2000; Deglon et al., 2000; Mandel et al., 1999). In some circumstances, it would be advantageous if the vector had (4) a regulatable transcriptional unit and (5) the ability to target a desired cell type (Jin et al., 1996; Sun et al., 2003). These additional modifications are the subject of ongoing experimentation. However, for current clinical use, it is not clear that all of these requirements must be presently met. Each vector has particular advantages and disadvantages and researchers worldwide are focusing on improving and developing each of these vector systems to optimize gene delivery and minimize toxicity. This ability of vectors to be delivered in a site-specific fashion might diminish or eliminate side effects that result from peripherally administered drugs acting at unintended targets. The present review will examine the use of the in vivo gene delivery systems in animal models of PD and discuss the relative strengths and weaknesses of each approach.