Biomedical subjects

S Behrstock

Publications and source records attributed to S Behrstock.

3 recordsLinked to original sources

PubMed2006

Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase the survival and functioning of dopamine neurons in a variety of animal models and some recent human trials. However, delivery of any protein to the brain remains a challenge due to the blood/brain barrier. Here we show that human neural progenitor cells (hNPC) can be genetically modified to release glycosylated GDNF in vitro under an inducible promoter system. hNPC-GDNF were transplanted into the striatum of rats 10 days following a partial lesion of the dopamine system. At 2 weeks following transplantation, the cells had migrated within the striatum and were releasing physiologically relevant levels of GDNF. This was sufficient to increase host dopamine neuron survival and fiber outgrowth. At 5 weeks following grafting there was a strong trend towards functional improvement in transplanted animals and at 8 weeks the cells had migrated to fill most of the striatum and continued to release GDNF with transport to the substantia nigra. These cells could also survive and release GDNF 3 months following transplantation into the aged monkey brain. No tumors were found in any animal. hNPC can be genetically modified, and thereby represent a safe and powerful option for delivering growth factors to specific targets within the central nervous system for diseases such as Parkinson's.

Animals↗

PubMed2003

Brain implantations of engineered GABA-releasing cells suppress tremor in an animal model of Parkinsonism.

Traditional approaches in the treatment of Parkinson's disease have typically been directed at restoring dopaminergic tone in the neostriatum of the basal ganglia. Nevertheless, the vast majority of neostriatal efferent projections use GABA as their neurotransmitter. Substantia nigra pars reticulata (SNr) is a major basal ganglia output area that is a target of these GABAergic projections, and research from animal models has indicated that stimulation of GABA receptors in SNr can produce motor effects consistent with an antiparkinsonian action. In the present study, implantation of engineered GABA-releasing cells into SNr reduced tremulous movements in an animal model of parkinsonian tremor. These results suggest that implantation of GABA cells into SNr, or possibly into other basal ganglia structures, could provide an alternative transplantation strategy for the treatment of Parkinsonism.

Animals↗

PubMed2000

Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures.

Transplantation of genetically engineered cells can provide sustained focal delivery of naturally occurring molecules, including neurotransmitters and growth factors. We have engineered immortalized mouse cortical neurons and glia to deliver GABA by driving GAD(65) expression. Engineered cell lines showed GAD(65) mRNA expression, enzymatic activity, and GABA release. In vitro, basal flux of GABA was approximately 20% of total cellular GABA. We transplanted these GABA-producing cells bilaterally into either the anterior or the posterior substantia nigra of 43 rats. The rats were subsequently kindled through an electrode placed in the entorhinal cortex. GABA-producing cells, but not beta-galactosidase-producing cells, affected kindling rates. The number of stimulations needed to reach the first stage-5 seizure and to achieve full kindling differed significantly between the anterior and posterior transplantation sites when GAD(65)-producing cells were transplanted but not when beta-galactosidase-producing cells were transplanted. Our data show that transplanted engineered cells can make and release GABA at physiologically meaningful concentrations.

Animals↗