Future Therapies – How Close is Tomorrow? Figure 1: Strategies for the Restoration of Dopamine Synthesis Capacity4
Dopamine replacement GTP
Tyr Tyr BH4 DOPA DA DOPA DA DOPA AADC DA
Post-synaptic spine of DA synapse
DA 5-HT L-DOPA Spared dopaminergic or sertonergic terminal
Post-synaptic spine of DA synapse
Post-synaptic spine of DA synapse
L-DOPA DA
Continuous levodopa delivery GTP
BH4 DOPA L-DOPA Pro-drug approach for dopamine production DA
• Three or novel not approved vectors needed
• Ectopic dopamine production possible (dyskinesia? neurodegeneration?) • No clinical data yet
• Two or novel not approved vectors needed
• Continuous levodopa levels in putamen (no dyskinesia?) • Encouraging preclinical data • No clinical data yet
5HT = 5-hydroxytryptamine; AADC = aromatic L-amino acid decarboxylase; BH4 = tetrahydrobiopterin ; DA = dopamine; DOPA = dihydroxyphenylalanine; GCH1 = GTP cyclohydrolase I; L-DOPA = levodopa; TH = tyrosine hydrolase; Tyr = tyrosine. Copyright (2009) with permission from Elsevier.
Across all strategies, the viral vectors are implanted or injected into the striatum to induce the production of proteins solely in the striatal neurons (not the dopaminergic neurons). The dopamine replacement strategy may confer a risk of dyskinesia or enhanced neurodegeneration due to excess dopamine, whereas in the continuous levodopa delivery approach, levodopa is metabolised to dopamine, and therefore, there is less likelihood of dyskinesia.
To date, clinical data exist only for one of the three possible dopamine replacement strategies; that is, the pro-drug approach. A recently published open-label, non-placebo-controlled clinical trial evaluated the safety and tolerability of AADC expression (introduced via AAV2) in 10 patients with PD (five received a high dose and five received a low dose).5
(relies on the introduction of three genes that will result in the production of dopamine); continuous levodopa delivery (intrastriatal gene transfer of the dopamine-synthetic enzyme tyrosine hydrolase [TH] combined with the exogenous administration of the cofactor for TH, tetrahydrobiopterin, or with co-expression of its rate-limiting synthetic enzyme, GTP cyclohydrolase 1); and a pro-drug approach for dopamine production (introduce one gene encoding the enzyme aromatic L-amino acid decarboxylase [AADC] to metabolise exogenous levodopa to dopamine).4
Modulating Basal Ganglia Circuitries
Significant improvements in UPDRS scores were observed at three months and these persisted until 12 months after surgery. There was a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and there was a correlation between motor scores and brain metabolism.7
No gene
therapy-related adverse events were observed. Results from an ongoing Phase II trial are expected in 2011.
In a subgroup of patients (n=5), positron emission tomography imaging confirmed expression of the AADC enzyme six months post-introduction in the high- and low-dose patient cohorts.6 Although the gene therapy was generally well tolerated, a safety concern was the high frequency of operation-induced adverse events, primarily three reports of intracranial haemorrhage (30 % of patients) and self-limited headache.5
The results revealed an approximately 30 % improvement in motor score (total Unified Parkinson’s Disease Rating Scale [UPDRS] and UPDRS III) both off and on medication and no relevant induction in dyskinesia.5
It remains unclear whether the risk of
intracranial bleeding is higher with gene therapy than with other neurosurgical procedures such as DBS.
Clearly, the efficacy and safety of the three strategies for dopamine replacement via gene therapy require further clinical studies.
EUROPEAN NEUROLOGICAL REVIEW SUPPLEMENT
Disease Modification with Gene Therapy Two trials, to date, have evaluated the gene therapy approach of disease modification by neurotrophic factor delivery (AAV2- associated introduction of neurturin [CERE-120]) into the putamen. This approach aims to promote sprouting from the remaining dopaminergic neurons and to slow disease progression by reducing cell death. A Phase I safety trial involved 12 patients with PD, and results showed no clinically significant adverse events, and a 36 % improvement in UPDRS III score and increased ‘on’ time without troublesome dyskinesia.8
However, this study was followed by a
placebo-controlled, double-blind Phase II trial of 58 patients with PD, which failed to reach the pre-defined clinical endpoint of symptomatic relief after 12 months‘ follow-up (published data are awaited). In light of the observed preliminary findings from these disease modification studies, points for consideration are:
•
Are the results from pre-clinical studies translatable to humans? Are the right animal models being used?
33
The gene therapy strategy of modulating basal ganglia circuitries involves the delivery of the glutamic acid decarboxylase (GAD) gene into the subthalamic nucleus via the AAV2 vector. The resulting increase in the GAD enzyme results in increased levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) within the subthalamic nucleus. GABA inhibits activity in this region, thereby reproducing the effects of STN-DBS (and restoring normal physiological function to the basal ganglia circuitry). Results were favourable in a Phase I safety trial using this gene therapy in 12 patients with PD.7
• See text for details
GCH1
GCH1
AADC
TH
TH
AADC
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