Cell and Gene Therapy for Parkinson's Disease: Therapeutic Effect and Modulation of Dyskinesias in the 6-OHDA Rat Model

Sammanfattning: The main pathological feature in Parkinson's disease is the progressive loss of dopamine neurons in the midbrain, which in turn leads to the appearance of motor deficits such as akinesia/bradykinesia (loss/slowness of movements), rigidity, postural imbalance and tremor. To this day, there is no cure for the disease, but there are medications to relieve the symptoms. The gold standard medication is the administration of the precursor of dopamine, L-DOPA, which is very efficient within the first years. Unfortunately, for the majority of the patients, this medication later leads to the development of abnormal involuntary movements, termed dyskinesias. These L-DOPA-induced dyskinesias are suggested to develop due to the route of the oral administration of the medication, which gives rise to intermittent and high fluctuations in the brain dopamine levels. Support for this has come from studies showing that continuous delivery of L-DOPA decreases the severity and magnitude of these side effects. In order to restore lost dopamine circuitry, fetal cell transplantation has been investigated as a potential treatment. The outcome of clinical trials has been highly variable, where some patients have shown very good response, while others displayed only marginal improvements to even a worsening of the L-DOPA-induced side effects. In addition, some patients have also experienced a new type of graft-induced dyskinesias in absence of any L-DOPA medication. In this thesis work, I have investigated the role of the progressive neurodegeneration on the functional improvement, as well as the development and maintenance of L-DOPA- and graft-induced dyskinesias, after fetal cell transplantation in the 6-hydroxydopamine rat model of Parkinson's disease. Dyskinesias, in particular, have been studied in regard to graft placement and the role of the serotonin neurons in the graft as well as the role of the host serotonin system. In addition, I have investigated if continuous delivery of DOPA (endogenous L-DOPA) by viral vector-mediated gene transfer, of the dopamine-dependent enzymes tyrosine hydroxylase and GTP cyclohydrolase 1, can reverse L-DOPA-induced dyskinesias. The results demonstrate that progression of the DA lesion outside striatal areas can be detrimental for the functional impact of the fetal cell transplantation. Moreover, the location of the transplanted neurons in the striatum, and the presence of serotonin neurons in the grafted tissue may have an impact on development and maintenance of L-DOPA-induced dyskinesias. Finally, viral vector gene delivery strategy to replace DOPA in the striatum can effectively improve behavior function and reduce L-DOPA-induced dyskinesia in the rat model of Parkinson's disease. This novel gene therapy treatment hold great promise for future clinical applications.