Long-term phenotypic correction of rodent hemiparkinsonism by gene therapy using genetically modified myoblasts

Cao, Lei; Zhao, Ying-Chun; Jiang, Zhihua; Xu, Danke; Liu, Z G; Chen, S D; Liu, X Y; Zheng, Zhiming

doi:10.1038/sj.gt.3301096

Cited by 13 publications

(7 citation statements)

References 32 publications

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“…Several studies have indicated that transfected primary myoblasts grafted into the CNS survive and maintain transgene expression up to several weeks [33, 38]. Tyrosine‐hydroxylase (TH)‐expressing myoblasts transplanted into the striata of 6‐OHDA‐lesioned rats were reported to result in pronounced TH expression as well as long‐term amelioration of Parkinsonian symptoms [39]. While these studies document the applicability of myoblast transplantation for localized gene delivery, widespread cell‐based gene transfer to the CNS has remained a challenge.…”

Section: Discussionmentioning

confidence: 99%

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Migration and Differentiation of Myogenic Precursors Following Transplantation into the Developing Rat Brain

et al. 2003

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There is increasing evidence that muscle-derived precursor cells can, under appropriate conditions, give rise to other than myogenic cell types. Transplantation into the embryonic ventricular zone provides a unique opportunity to study the migration and differentiation of non-neural somatic progenitor cells in response to instructive cues within the developing neuroepithelium. Here, we demonstrate that myogenic cell lines grafted into the ventricles of rat embryos showed widespread migration into several host brain compartments. In contrast to incorporation patterns observed after transplantation of neural cells, grafted myoblasts incorporated virtually exclusively along endogenous blood vessels. Preferential incorporation sites included cortex, olfactory bulb, hippocampus, striatum, thalamus, hypothalamus, and tectum. While the engrafted myoblasts showed no evidence of neural differentiation, a fraction exhibited pronounced coexpression of endothelial marker antigens. These findings support the concept of a close developmental relationship between the myogenic and the endothelial lineages. Used as a delivery system, transfected myoblasts may be exploited for widespread gene transfer to the perivascular compartment of the perinatal central nervous system. Sigmund-Freud-Str. 25, D -53105 Bonn, Germany. Telephone: 49-228-287-9508; Fax 49-228-287-9883; e-mail: brustle @uni-bonn.de Received August 9, 2002; accepted for publication September 30, 2002. ©AlphaMed Press 1066-5099/2003 INTRODUCTIONThe results of several recent studies indicate that the differentiation potential of adult stem cells is broader than previously assumed. Following bone marrow transplantation in mice, donor-derived cells have been found to enter the central nervous system (CNS) and express markers of glia [1] and neurons [2, 3]. A single bone marrow stem cell was recently shown to give rise to skin, lung, and gastrointestinal epithelium [4]. Juvenile and adult rodent skin cells can be differentiated in vitro into cells bearing antigens

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Section: Discussionmentioning

confidence: 99%

“…Double labelings were confirmed by digital reconstruction in the x-z and y-z planes. [39]. While these studies document the applicability of myoblast transplantation for localized gene delivery, widespread cell-based gene transfer to the CNS has remained a challenge.…”

Section: Figure 6 Confocal Laser Scanning Microscopy Confirming the mentioning

confidence: 99%

Migration and Differentiation of Myogenic Precursors Following Transplantation into the Developing Rat Brain

et al. 2003

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“…[28][29][30] These cells are capable of producing and releasing levodopa when exogenous BH 4 is added to the culture medium, and, when implanted in 6-OHDA-lesioned rats, behavioral recovery was observed. [32] In both reports, behavioral recovery was observed. Based on this concept, other cell types, such as myoblasts, [31,32] were also engineered to express TH.…”

Section: Symptomatic Therapymentioning

confidence: 90%

Gene Therapy for Parkinson??s Disease

Segovia

2002

American Journal of PharmacoGenomics

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Parkinson's disease appears to be a good candidate for gene therapy. The primary biochemical defect associated with the disease has been clearly determined as an absence of dopamine in the caudate-putamen, and the anatomical region where the neuropathologic hallmark of the disease, death of the nigral dopamine-producing neurons, occurs, remains circumscribed. Based on the biochemical and anatomical information gathered on Parkinson's disease, different gene therapy strategies have been devised to treat it. The first, and most explored strategy so far, consists in engineering cells to produce levodopa or dopamine so they will replace dopaminergic neurotransmission. Several types of cells have been employed in these experiments, and behavioral recovery has been reported in animal models of the disease. However, this approach cannot prevent neuronal death, nor reconstruct brain circuits. Another strategy is to protect cells by transferring genes that encode neurotrophic factors. Effort is now being concentrated into this research area, and promising results have recently been reported. Finally, an additional strategy aims at generating cells with a dopaminergic phenotype so they will be capable of replacing the missing dopaminergic neurons in biochemical, anatomical and functional terms. This has the potential to become an important constituent for an effective cure. Gene therapy holds significant promise for the treatment of neurodegenerative disorders, and Parkinson's disease treatment will benefit greatly from the knowledge and information arising from gene therapy research.

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“…Interestingly, myoblasts have been transfected with TH alone and stably produce dopamine for more than a year after striatal injection which reduces apomorphine-induced rotation of 6-OHDA-lesioned rats by 50% (Cao et al 2000); no apparent proliferation of grafted cells has been noted. Moreover, positive results from GDNF-expressing encapsulated myoblasts have been reported (Zurn et al 2001).…”

Section: Gene-modified Grafts From Non-neuronal Sourcesmentioning

confidence: 98%

Gene therapy in Parkinson?s disease

Eberhardt

Schulz

2004

Cell Tissue Res

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Gene therapy in Parkinson's disease appears to be at the brink of the clinical study phase. Future gene therapy protocols will be based on a substantial amount of preclinical data regarding the use of ex vivo and in vivo genetic modifications with the help of viral or non-viral vectors. To date, the supplementation of neurotrophic factors and substitution for the dopaminergic deficit have formed the focus of trials to achieve relief in animal models of Parkinson's disease. Newer approaches include attempts to influence detrimental cell signalling pathways and to inhibit overactive basal ganglia structures. Nevertheless, current models of Parkinson's disease do not mirror all aspects of the human disease, and important issues with respect to long-term protein expression, choice of target structures and transgenes and safety remain to be solved. Here, we thoroughly review available animal data of gene transfer in models of Parkinson's disease.

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Long-term phenotypic correction of rodent hemiparkinsonism by gene therapy using genetically modified myoblasts

Cited by 13 publications

References 32 publications

Migration and Differentiation of Myogenic Precursors Following Transplantation into the Developing Rat Brain

Migration and Differentiation of Myogenic Precursors Following Transplantation into the Developing Rat Brain

Gene Therapy for Parkinson??s Disease

Gene therapy in Parkinson?s disease

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