Gene therapy to the rescue in Parkinson's disease

Several important caveats need to be considered before this approach could be widely used in PD patients. Questions regarding the safety of lentiviruses need be addressed before human studies are undertaken because one animal from both the lenti-β-gal and lenti-GDNF groups died within one week after administration of the virus. Although no definitive cause of death was identified, necropsies revealed mild necrosis from multifocal random hepatocellular coagulation in both animals 4xNeurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Kordower, J.H et al. Science. 2000; 290: 767–773Crossref | PubMed | Scopus (950)See all References4. It is important to mention that no ill effects were observed on necropsy in the remaining surviving animals, nor were ill effects observed in other primate lentiviral studies.It is also not clear if lentiviral gene expression will last throughout the lifetime of a PD patient. Current therapies for PD allow patients to live normal life spans. In the study by Kordower et al., a benefit of at least eight months was demonstrated and even though this would have profound effects in PD patients, PD is a progressive disease and thus GDNF might need to be produced throughout the lifetime of a patient. Only 75% of the surviving animals showed functional improvements despite effective delivery and expression of GDNF; thus, optimization of the timing and locations as well as the number of injections need to be clarified before human trials can begin. In rodent models of PD, GDNF injections into the substantia nigra alone tend to spare only DA-containing neurons, but do not restore DA concentrations in the striatum 7xGDNF: a novel factor with therapeutic potential for neurodegenerative disorders. Walton, K.M. Mol. Neurobiol. 1999; 19: 43–59Crossref | PubMedSee all References, 8xGlial cell line-derived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson's disease. Grondin, R and Gash, D.M. J. Neurol. 1998; 245: 35–42CrossrefSee all References. Striatal GDNF appears to be the most important for functional reinnervation to occur because in most studies DA-containing terminals are spared and protection is conferred to DA-containing neurons in the substantia nigra 7xGDNF: a novel factor with therapeutic potential for neurodegenerative disorders. Walton, K.M. Mol. Neurobiol. 1999; 19: 43–59Crossref | PubMedSee all References, 8xGlial cell line-derived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson's disease. Grondin, R and Gash, D.M. J. Neurol. 1998; 245: 35–42CrossrefSee all References. The effects of intrastriatal GDNF elicited in the substantia nigra are probably due to retrograde transport of GDNF (7xGDNF: a novel factor with therapeutic potential for neurodegenerative disorders. Walton, K.M. Mol. Neurobiol. 1999; 19: 43–59Crossref | PubMedSee all References, 8xGlial cell line-derived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson's disease. Grondin, R and Gash, D.M. J. Neurol. 1998; 245: 35–42CrossrefSee all References). Thus, efforts might need to focus on the delivery of lenti-GDNF to DA-containing terminal fields, such as the striatum.Potential side-effects of GDNF also exist. In i.c.v. delivery experiments, a high dose of GDNF was associated with dyskinesias in MPTP-induced parkinsonian monkeys 13xDose response to intraventricular glial cell line-derived neurotrophic factor administration in parkinsonian monkeys. Zhang, Z et al. J. Pharmacol. Exp. Ther. 1997; 282: 1396–1401PubMedSee all References13, and unexplained weight loss has been encountered in monkeys receiving i.c.v. delivery of GDNF or delivery of GDNF directly to the substantia nigra. Furthermore, humans have experienced a variety of side-effects including nausea, loss of appetite, hallucinations and depression 9xClinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease. Kordower, J.H et al. Ann. Neurol. 1999; 46: 419–424Crossref | PubMed | Scopus (307)See all References9. Thus, the ability to tightly control GDNF expression and/or activity might be required to fine-tune the actions of GDNF to optimize the therapeutic response and minimize potential side-effects.PD patients and clinicians have been anxiously awaiting the development of a proven and safe protective, regenerative and restorative therapy to slow or reverse the degenerative effects of PD, and lentiviral-mediated delivery of GDNF might fit the request. A few hurdles need to be overcome before its clinical use, but these can be readily addressed and overcome with further investigations and advances. Additionally, other vehicles might be able to deliver neurotrophic factors and neuroprotectants (e.g. engineered cells). Ultimately, the future looks bright for powerful new therapies for the treatment of PD, which might offer PD patients the protective, regenerative and restorative therapy to slow or reverse the degenerative effects of this disease. Furthermore, these approaches might be of value in other neurodegenerative diseases.