| 1. |
- Björklund, Tomas, et al.
(author)
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Gene therapy for dopamine replacement.
- 2010
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In: Progress in Brain Research. - 1875-7855. ; 184, s. 221-235
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Research review (peer-reviewed)abstract
- Dopamine replacement for Parkinson's disease (PD) have seen three major iterations of improvements since the introduction of l-3,4-dihydroxyphenylalanine (l-DOPA) pharmacotherapy: dopamine receptor agonists, ex vivo gene transfer for cell transplantation and most recently in vivo gene therapy. In this chapter, we describe the principles behind viral vector-mediated enzyme replacement in PD. We focus on the enzymes involved in the dopamine synthesis and their internal regulation, the early experimental work on gene therapy using different viral vector types and selection of transgenes, and finally discuss the recently completed early phase clinical trials in PD patients.
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| 2. |
- Björklund, Tomas, et al.
(author)
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Optimized adeno-associated viral vector-mediated striatal DOPA delivery restores sensorimotor function and prevents dyskinesias in a model of advanced Parkinson's disease.
- 2010
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In: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 133:Pt 2, s. 496-511
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Journal article (peer-reviewed)abstract
- Viral vector-mediated gene transfer utilizing adeno-associated viral vectors has recently entered clinical testing as a novel tool for delivery of therapeutic agents to the brain. Clinical trials in Parkinson's disease using adeno-associated viral vector-based gene therapy have shown the safety of the approach. Further efforts in this area will show if gene-based approaches can rival the therapeutic efficacy achieved with the best pharmacological therapy or other, already established, surgical interventions. One of the strategies under development for clinical application is continuous 3,4-dihydroxyphenylalanine delivery. This approach has been shown to be efficient in restoring motor function and reducing established dyskinesias in rats with a partial lesion of the nigrostriatal dopamine projection. Here we utilized high purity recombinant adeno-associated viral vectors serotype 5 coding for tyrosine hydroxylase and its co-factor synthesizing enzyme guanosine-5'-triphosphate cyclohydrolase-1, delivered at an optimal ratio of 5 : 1, to show that the enhanced 3,4-dihydroxyphenylalanine production obtained with this optimized delivery system results in robust recovery of function in spontaneous motor tests after complete dopamine denervation. We found that the therapeutic efficacy was substantial and could be maintained for at least 6 months. The tyrosine hydroxylase plus guanosine-5'-triphosphate cyclohydrolase-1 treated animals were resistant to developing dyskinesias upon peripheral l-3,4-dihydroxyphenylalanine drug challenge, which is consistent with the interpretation that continuous dopamine stimulation resulted in a normalization of the post-synaptic response. Interestingly, recovery of forelimb use in the stepping test observed here was maintained even after a second lesion depleting the serotonin input to the forebrain, suggesting that the therapeutic efficacy was not solely dependent on dopamine synthesis and release from striatal serotonergic terminals. Taken together these results show that vector-mediated continuous 3,4-dihydroxyphenylalanine delivery has the potential to provide significant symptomatic relief even in advanced stages of Parkinson's disease.
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| 3. |
- Cederfjäll, Erik, et al.
(author)
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Continuous DOPA synthesis from a single AAV: dosing and efficacy in models of Parkinson's disease.
- 2013
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 3
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Journal article (peer-reviewed)abstract
- We used a single adeno-associated viral (AAV) vector co-expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) to investigate the relationship between vector dose, and the magnitude and rate of recovery in hemi-parkinsonian rats. Intrastriatal injections of >1E10 genomic copies (gc) of TH-GCH1 vector resulted in complete recovery in drug-naïve behavior tests. Lower vector dose gave partial to no functional improvement. Stereological quantification revealed no striatal NeuN+ cell loss in any of the groups, whereas a TH-GCH1 dose of >1E11 gc resulted in cell loss in globus pallidus. Thus, a TH-GCH1 dose of 1E10 gc gave complete recovery without causing neuronal loss. Safety and efficacy was also studied in non-human primates where the control vector resulted in co-expression of the transgenes in caudate-putamen. In the TH-GCH1 group, GCH1 expression was robust but TH was not detectable. Moreover, TH-GCH1 treatment did not result in functional improvement in non-human primates.
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| 4. |
- Cederfjäll, Erik, et al.
(author)
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Controlled striatal DOPA production from a gene delivery system in a rodent model of Parkinson's disease.
- 2015
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 23:5, s. 896-906
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Journal article (peer-reviewed)abstract
- Conventional symptomatic treatment for Parkinson's disease (PD) with long term L-DOPA is complicated with development of drug-induced side effects. In vivo viral vector-mediated gene expression encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) provides a drug delivery strategy of DOPA with distinct advantages over pharmacotherapy. Since the brain alterations made with current gene transfer techniques are irreversible, the therapeutic approaches taken to the clinic should preferably be controllable to match the needs of each individual during the course of their disease. We used a recently described tunable gene expression system based on the use of destabilized dihydrofolate reductase (DD) and generated a N-terminally coupled GCH1 enzyme (DD-GCH1) while the TH enzyme was constitutively expressed, packaged in adeno-associated viral (AAV) vectors. Expression of DD-GCH1 was regulated by the activating ligand trimethoprim (TMP) that crosses the blood-brain barrier. We show that the resulting intervention provides a TMP-dose dependent regulation of DOPA synthesis that is closely linked to the magnitude of functional effects. Our data constitutes the first proof of principle for controlled reconstitution of dopamine capacity in the brain and suggests that such next generation gene therapy strategies are now mature for pre-clinical development towards use in patients with PD.Molecular Therapy (2015); doi:10.1038/mt.2015.8.
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| 5. |
- Cederfjäll, Erik, et al.
(author)
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Design of a Single AAV Vector for Coexpression of TH and GCH1 to Establish Continuous DOPA Synthesis in a Rat Model of Parkinson's Disease.
- 2012
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 20:7, s. 1315-1326
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Journal article (peer-reviewed)abstract
- Preclinical efficacy of continuous delivery of 3,4-dihydroxyphenylalanine (DOPA) with adeno-associated viral (AAV) vectors has recently been documented in animal models of Parkinson's disease (PD). So far, all studies have utilized a mix of two monocistronic vectors expressing either of the two genes, tyrosine hydroxylase (TH) and GTP cyclohydrolase-1 (GCH1), needed for DOPA production. Here, we present a novel vector design that enables efficient DOPA production from a single AAV vector in rats with complete unilateral dopamine (DA) lesions. Functional efficacy was assessed with drug-induced and spontaneous motor behavioral tests where vector-treated animals showed near complete and stable recovery within 1 month. Recovery of motor function was associated with restoration of extracellular DA levels as assessed by online microdialysis. Histological analysis showed robust transgene expression not only in the striatum but also in overlying cortical areas. In globus pallidus, we noted loss of NeuN staining, which might be due to different sensitivity in neuronal populations to transgene expression. Taken together, we present a single AAV vector design that result in efficient DOPA production and wide-spread transduction. This is a favorable starting point for continued translation toward a therapeutic application, although future studies need to carefully review target region, vector spread and dilution with this approach.
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| 6. |
- Cederfjäll, Erik, et al.
(author)
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Key factors determining the efficacy of gene therapy for continuous DOPA delivery in the Parkinsonian brain
- 2012
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 48:2, s. 222-227
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Research review (peer-reviewed)abstract
- L-DOPA is currently the standard treatment for alleviating the motor symptoms in Parkinson's disease. The therapeutic efficacy, however, diminishes as the disease progresses. It has been suggested that the beneficial effect of L-DOPA could be reestablished by changing the mode of administration. Indeed, continuous delivery of L-DOPA has been shown to be an effective way to circumvent many of the side effects seen with traditional oral administration, which results in an intermittent supply of the dopamine precursor to the brain. However, all currently tested continuous dopaminergic stimulation approaches rely on peripheral administration. This is not ideal since it gives rise to off target effects and is difficult to maintain long-term. Thus, there is an unmet need for an effective continuous administration method with an acceptable side effect profile. Viral-mediated gene therapy is a promising alternative paradigm that can meet this demand. Encouraging preclinical studies in animal models of Parkinson's disease showed therapeutic efficacy after expression of the genes encoding the enzymes required for biosynthesis of dopamine. Although the first phase I clinical trials using these approaches have been conducted, clear positive data in placebo controlled efficacy studies is still lacking. We are now at a critical junction and need to carefully review the preclinical data from the clinical translation perspective and identify the key factors that will determine the potential for success in gene therapy for Parkinson's disease. (C) 2011 Published by Elsevier Inc.
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| 7. |
- Cederfjäll, Erik
(author)
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Novel strategies for enzyme replacement with gene therapy in models of Parkinson’s disease
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Parkinson’s disease is a brain disorder characterized by loss of dopaminergic neurons in the midbrain, resulting in the characteristic motor symptoms: resting tremor, rigidity, akinesia and postural instability. Symptomatic treatment is based on reconstituting the loss of dopamine in the brain, primarily by oral administration of its precursor L-DOPA. Although this drug is effective in the early years of treatment, patients experience troublesome side effects over time that are believed to develop at least partly due to route of administration in addition to the progressive worsening of the disease. An alternative to oral L-DOPA administration is continuous DOPA synthesis with gene therapy. This can be achieved by expressing enzymes needed for DOPA synthesis in neurons in the striatum, where the loss of dopamine is most profound in Parkinson’s disease. The addition of two enzymes is necessary for efficient synthesis of DOPA in striatal neurons, namely tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1), and these can be delivered with an adeno-associated virus (AAV) vector. In the first two studies in this thesis, a new AAV vector design including TH and GCH1 was developed and validated in a rat model of Parkinson’s disease. Expression of this vector in parkinsonian rats resulted in complete recovery in different tests of motor function and was dose dependent. The therapeutic efficacy in this model was associated with increased levels of DOPA and dopamine in the striatum and histological analysis showed widespread expression of both enzymes. The vector was also tested in a non-human primate model of Parkinson’s disease that showed safety but not efficacy. The aim of the third study in this thesis was to implement a regulation mechanism for the continuous DOPA synthesis approach. This is a long-standing goal for gene therapy and the strategy used here was based on destabilizing domains (DD) and the ligand trimethoprim (TMP). Combining DD regulation with the continuous DOPA synthesis approach resulted robust efficacy in parkinsonian rats when given TMP. In addition, the basal expression in absence of the TMP ligand was minimal. Efficacy of this approach should now be validated in nonhuman primates before clinical translation can begin.
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| 8. |
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| 9. |
- Kirik, Deniz, et al.
(author)
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Gene therapy for Parkinson's disease : Disease modification by GDNF family of ligands
- 2017
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 97, s. 179-188
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Research review (peer-reviewed)abstract
- Gene transfer is a promising drug delivery method of advanced therapeutic entities for Parkinson's disease. One advantage over conventional therapies, such as peripheral delivery of the dopamine pre-cursor L-DOPA, is site-specific expression of proteins with regenerative, disease-modifying and potentially neuroprotective capacity. Several clinical trials have been performed to test the capacity of glial-cell line derived neurotrophic factor and neurturin to rescue degenerating dopaminergic neurons in the substantia nigra and their axon terminals in the striatum by delivery of these neurotrophic factors either as purified protein or by means of viral vector mediated gene delivery to the brain. Although gene therapy approaches tested so far have been shown to be safe, none met their primary endpoints in phase II clinical trials designed and powered to test the efficacy of the intervention. Within the scope of this review we aim to describe the state-of-the-art in the field, how different technical parameters were translated from pre-clinical studies in non-human primates to clinical trials, and what these trials taught us regarding important factors that may pave the way to the success of gene therapy for the treatment of Parkinson's disease.
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