Transient striatal delivery of GDNF via encapsulated cells leads to sustained behavioral improvement in a bilateral model of Parkinson disease

Ecole Polytechnique Fédérale de Lausanne, EPFL, Integrative Bioscience Institute, CH-1015 Lausanne, Switzerland.
Neurobiology of Disease (Impact Factor: 5.08). 05/2006; 22(1):119-29. DOI: 10.1016/j.nbd.2005.10.006
Source: PubMed


Numerous studies have shown the neuroprotective and regenerative benefits of glial cell line-derived neurotrophic factor (GDNF) in animal models of PD. Brain delivery of GDNF can, however, be associated with limiting side-effects in both primates and PD patients, rendering the duration of delivery a critical factor. In the present study, the effects of transient vs. sustained GDNF delivery by encapsulated cells were evaluated in a bilateral animal model, closely mimicking advanced PD. One week following bilateral striatal 6-hydroxydopamine injections in rats, capsules loaded with human fibroblasts genetically engineered to release GDNF were bilaterally implanted in the striatum. GDNF delivery resulted in a significant improvement of movement initiation and swimming performance in the lesioned animals, associated with striatal reinnervation of dopaminergic fibers. To test the sustainability of the behavioral improvement, GDNF-secreting capsules were withdrawn in a subgroup of animals, 7 weeks post-implantation. Strikingly, both the behavioral and morphological improvements were maintained until the sacrifice of the animals 6 weeks post-GDNF withdrawal. The sustained cellular and behavioral benefits after GDNF washout suggest the need for temporary delivery of the trophic factor in PD. Retrievable encapsulated cells represent an attractive delivery tool to achieve this purpose.

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    • "Parkinsonian symptoms are characterized by severe tremor, rigidity, bradykinesia, and postural instability.22 In particular, glial cell line-derived neurotrophic factor (GDNF) has been shown to be the most potent protective molecule for dopaminergic nigral neurons.23 GDNF has received particular attention because it can support the survival of dopaminergic midbrain neurons and therefore may provide a therapy for Parkinson’s disease. "
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    ABSTRACT: Parkinson's disease is known to result from the loss of dopaminergic neurons. Direct intracerebral injections of high doses of recombinant glial cell line-derived neurotrophic factor (GDNF) have been shown to protect adult nigral dopaminergic neurons. Because GDNF does not cross the blood-brain barrier, intracerebral gene transfer is an ideal option. Chitosan (CHI) is a naturally derived material that has been used for gene transfer. However, the low water solubility often leads to decreased transfection efficiency. Grafting of highly water-soluble polyethylene imines (PEI) and polyethylene glycol onto polymers can increase their solubility. The purpose of this study was to design a non-viral gene carrier with improved water solubility as well as enhanced transfection efficiency for treating Parkinsonism. Two molecular weights (Mw =600 and 1,800 g/mol) of PEI were grafted onto CHI (PEI600-g-CHI and PEI1800-g-CHI, respectively) by opening the epoxide ring of ethylene glycol diglycidyl ether (EX-810). This modification resulted in a non-viral gene carrier with less cytotoxicity. The transfection efficiency of PEI600-g-CHI/deoxyribonucleic acid (DNA) polyplexes was significantly higher than either PEI1800-g-CHI/DNA or CHI/DNA polyplexes. The maximal GDNF expression of PEI600-g-CHI/DNA was at the polymer:DNA weight ratio of 10:1, which was 1.7-fold higher than the maximal GDNF expression of PEI1800-g-CHI/DNA. The low toxicity and high transfection efficiency of PEI600-g-CHI make it ideal for application to GDNF gene therapy, which has potential for the treatment of Parkinson's disease.
    International Journal of Nanomedicine 06/2014; 9(1):3163-74. DOI:10.2147/IJN.S60465 · 4.38 Impact Factor
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    • "Transplanted cell capsules provide a continuous and concentrated means of efficiently delivering secreted molecules locally, as opposed to systemic administration of single cell suspensions (Rabanel et al., 2009). Cell microencapsulation is particularly useful to treat dysfunction of metabolic or secretory tissues, including diseases such as diabetes, Parkinson's, hypoparathyroidism, and hemophilia (Hasse et al., 1997; Hortelano et al., 1996; Sajadi et al., 2006). Secretory disorders are often among the most difficult to address, as a continual regulation and response to stimuli is required. "
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    ABSTRACT: Cell microencapsulation has been utilized for decades as a means to shield cells from the external environment while simultaneously permitting transport of oxygen, nutrients, and secretory molecules. In designing cell therapies, donor primary cells are often difficult to obtain and expand to appropriate numbers, rendering stem cells an attractive alternative due to their capacities for self-renewal, differentiation, and trophic factor secretion. Microencapsulation of stem cells offers several benefits, namely the creation of a defined microenvironment which can be designed to modulate stem cell phenotype, protection from hydrodynamic forces and prevention of agglomeration during expansion in suspension bioreactors, and a means to transplant cells behind a semi-permeable barrier, allowing for molecular secretion while avoiding immune reaction. This review will provide an overview of relevant microencapsulation processes and characterization in the context ofmaintaining stem cell potency, directing differentiation, investigatingscalable production methods, and transplantingstem cells for clinically-relevant disorders. Biotechnol. Bioeng. © 2012 Wiley Periodicals, Inc.
    Biotechnology and Bioengineering 03/2013; 110(3). DOI:10.1002/bit.24802 · 4.13 Impact Factor
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    • "However, in these cases a significant increase in striatal dopaminergic innervation was still found, indicating that CB grafts had induced sprouting of the remaining nigrostriatal terminals. Nigrostriatal fiber outgrowth has been also reported to occur in preclinical studies using a variety of cell and gene therapy protocols with GDNF and other trophic factors (see, for example Björklund et al., 1997; Kirik et al., 2004; Sajadi et al., 2006; Tomac et al., 1995). Moreover, axonal sprouting has been reported in a postmortem study on a PD patient that had a striatal GDNF-delivery cannula implanted (Love et al., 2005). "
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    ABSTRACT: Intrastriatal transplantation of dopaminergic carotid body (CB) cells ameliorates parkinsonism in animal models and, with less efficacy, in Parkinson's disease patients. CB-based cell therapy was initially proposed because of its high dopamine content. However, later studies suggested that its beneficial effect might be due to a trophic action exerted on nigrostriatal neurons. Compatible with this concept are the high levels of neurotrophic factors encountered in CB cells. To test experimentally this idea, unilateral striatal transplants were performed with a sham graft in the contralateral striatum, as a robust internal control. Thereafter, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6, -tetrahydropyridine was injected during 3 months. CB grafts protected from degeneration ipsilateral nigral dopaminergic neurons projecting to the transplant in a dose-dependent manner regarding size and glial cell line-derived neurotrophic factor expression. Grafts performed at different times after the onset of the neurotoxic treatment demonstrated with histological and behavioral methods protection and repair of the nigrostriatal pathway by CB transplants. This study provides a mechanistic explanation for the action of CB transplants on parkinsonian models. It should also help to improve cell therapy approaches to Parkinson's disease.
    Neurobiology of aging 06/2012; 34(3). DOI:10.1016/j.neurobiolaging.2012.06.001 · 5.01 Impact Factor
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