Gene therapy for neurodegeneration

Abstract

Glial cell derived neutrophic factor (GDNF) has been shown to protect a wide range of neurons – including dopaminergic and motor neurons – from degeneration and death. This potent neuroprotective effect of GDNF has made it a prime candidate for consideration as a treatment for Parkinson's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and also spinal cord injuries. The direct administration of GDNF to the brain has proven difficult, and so several groups have recently attempted to deliver and express GDNF using adenovirus and adeno-associated viral vectors. Though these studies have shown successful gene transfer, and in a number of different model systems evidence for neuroprotection, a recent study using an HIV-1 based lentiviral vector has shown the most encouraging set of results to date 1. Kordower J.H et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science. 2000; 290: 767-773 Crossref PubMed Scopus (1116) Google Scholar . In the study by Kordower et al., two primate models of Parkinson's disease were used to assess the neuroprotective effect of GDNF. The lenti-GDNF vector (or a control lentiviral vector expressing a marker gene) was administered by stererotaxic injection of the striatum and substantia nigra. In both models, lentiviral derived GDNF expression was detected by immunostaining in brain sections. Expression was not only localized around the injection site but there was also evidence of anterograde transport of GDNF protein. Improvements were measured in two neurological markers of Parkinson's disease, and behavioral studies showed that monkeys who received lenti-GDNF one week after Parkinson's disease-inducing neurotoxin treatment significantly improved their performances in tests compared to control animals. No overt adverse effects associated with lentiviral administration were seen. Though substantial work is required before clinical trials can be considered, this study confirms that gene therapy using GDNF is a viable approach for the treatment of Parkinson's disease, and potentially several other neurodegenerative diseases.