Survey of Current Experimental Human Applications of Restorative Neurosurgery

Clinical application of cell implantation and gene transfer in human brain disorders has not reached the level of therapy. All treatments still are in the experimental phase as the beneficial functional outcomes are variable, unpredictable or not present at all. The following section surveys briefly the achievements in this area to date.

2.4.1 Parkinson's Disease

PD is primarily caused by the slow loss of dopaminergic neurons in the sub-stantia nigra so that their dopamine transmitter function in the striatum eventually disappears. PD is generally age-specific: approximately 1% of the population over age 60 develops the disease. An appropriate dopaminergic signal is vital for a smooth, coordinated function of the body's muscles and movement. As soon as approximately 80% of the dopamine-producing cells are lost, the symptoms of Parkinson's disease appear. The key signs of PD are tremor, slowness of movement, rigidity and loss of balance. Other signs of Parkinson's disease may include small, cramped handwriting, stiff facial expression, a shuffling walk, muffled speech and depression. Current pharmacological treatments with dopamine agonists and dopamine precursors reduce the symptoms in the early stages of the disease. However, with progress of the nigral degeneration, these drugs cease to be effective.

Dopamine cell supplementation began with open trials of striatal placement of the patient's own dopamine-producing adrenal medulla tissue (Backlund et al. 1985; Madrazo et al. 1987). This tissue was used experimentally as an alternative source of dopamine in order to circumvent the ethical problems following the use of human fetal brain tissue obtained from elective abortions (Boer 1996). The outcomes of this and later studies by other groups were disappointing and must be considered to have largely failed: not enough of the transplanted tissue survived, amelioration of the motor disturbances was absent or minor, and no relationship existed between dopaminergic cell survival and behavioural response. Other approaches of bypassing the use of human embryonic tissue have been tried, including cells obtained from the patient's own stellate ganglion but only modest anti-parkinsonian effects are reported in a small number of patients (Itakura et al. 1997). As a corollary of the above clinical results, as well as the significantly better functional effects of immature tissue transplants in the case of parkinsonian rats and monkeys, a move towards the use of human fetal dopaminergic neurons in patients was inevitable (Boer 1999).

Intracerebral transplantation of human fetal dopaminergic neuron-containing mesencephalic tissue fragments, or cell suspensions thereof, obtained from the remains of legally induced abortions, were placed in the dopamine-depleted caudate-putamen complex of late stage PD patients. So far, more than 300 patients with PD have undergone this allograft surgery, but under different conditions of donor tissue treatment, graft placement, surgical approach and pre- and post-grafting treatment and symptom evaluation. Months after the implantation surgery several clinical centres observed consistent and clinically meaningful benefits in small groups of patients in open trials using a relatively strict common protocol of pre- and post-surgery evaluation of graft survival and disease symptoms (Peschanski et al. 1994; Defer et al. 1996; Levivier et al. 1997; Mendez et al. 2002). Others, however, reported more variable or negative results (Freed et al. 1992; Lopez-Lozano et al. 1997). The benefits on the Unified Parkinson's Disease Rating Scale (UPDRS) often go hand in hand with dopaminergic cell survival as measured by fluoro-dopa PET scanning, which indicates graft survival.

Recently, the results of randomised double-blind sham surgery-controlled neurotransplantation studies in PD were published (sham surgery performed as a hole drilled in the outer layer of the skull bone but without penetration of a canula into the brain) (Freed et al. 2001, Olanow et al. 2003). At the outset, the design of such studies was criticised with respect to the fact that this large-scale study, including ~20 patients in each group, was performed at too early a stage, i.e., when optimal methods for tissue procurement, graft preparation and implantation had not yet been established (Widner 1994). The studies did, however, demonstrate that there was no lasting placebo effect, and that anti-parkinson effects were found primarily in the younger group of patients (Freed et al. 2001). Moreover, several patients in the treatment group developed abnormal involuntary movements and these movements were regarded as major side effects of this study. The modest improvement in neurological rating scores, only partly comparable with other studies (Isacson et al. 2001), and the occurrence of dyskinesias aroused widespread scientific interest and debate about the future of cell replacement therapies in PD (Brundin et al. 2001; Dunnett et al. 2001; Isacson et al. 2001). The fact that the study was double-blind and sham-controlled eased the initial methodological criticism and led the media to take these results as sound evidence that the technique of neural tissue transplantation in general was faulty and ineffective (Vogel 2001). This interpretation, however, is erroneous, as the net effects are dependent on the particular technique used (Bjorklund 2005). What was predicted by Widner and Defer (1999) became true: the results of a suboptimal grafting procedure challenged the therapeutic value of cell therapy in PD. Journalists called the results a failure, thereby harming the field that tries to develop novel cell replacement therapies in brain diseases (Dunnett et al. 2001). However, the field of experimental clinical neurotransplantation agreed that dopaminer-gic cell implantation in PD cannot be recommended as, or even be called, a therapy (Polgar et al. 2003). Further improvement of the technique is needed and the cause of the dopaminergic graft-related dyskinesias needs to be unraveled.

In addition to cellular therapies in PD, phase I studies are currently also being performed with AAV vector-mediated gene transfer, based on a series of successful studies with in vivo and ex vivo AAV and LV vector-mediated gene transfer in PD animal models (Raymon et al. 1997; Freese 1999; Kor-dower et al. 2000; Shen et al. 2000; Le and Frim 2002). One trial tries to mimic the results of deep brain stimulation (DBS) in the subthalamic nucleus (STN) of the brain. DBS is shown to be an effective method to treat many PD patients in the late stages of the disease when L-dopa medication starts to fail. The application of AAV-GAD vectors (containing the gene for glutamic acid decarboxylase [GAD], the enzyme synthesising the major inhibitory neurotransmitter gamma amino butyric acid [GABA] and upon overexpression causing a chronic release of GABA) in the animal STN results in similar result as electrical stimulation (During et al. 1998; 2001). According to the interim clinical findings (Feigin et al. 2005), AAV-GAD treatment in the STN appears to be safe and well-tolerated in advanced Parkinson's disease, with no evidence of adverse effects or immunologic reaction. One year after treatment, patients exhibited a 27% statistically significant improvement in motor function on the side of their body corresponding to the treated part of the brain, with no improvement for the untreated side. A second phase I clinical study uses AAV-AADC, a vector that introduces the gene for L-amino acid decarboxylase (AADC) in the striatum of PD patients (http://www.avigen.com, accessed on December 7th, 2006). This enzyme catalyses the synthesis of dopamine, and is known to decrease with progression of PD. In parkinsonian monkeys, the vector has been effectively applied (Bankiewicz et al. 2000; Sanftner et al. 2005) and may be of continuing clinical benefit (Bankiewicz et al. 2006).

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