Widespread Striatal Delivery of GDNF from Encapsulated Cells Prevents the Anatomical and Functional Consequences of Excitotoxicity

Abstract

Methods. Human ARPE-19 cells engineered to secrete high levels of the glial cell line-derived neurotrophic factor (GDNF) were encapsulated into hollow fiber membranes. The devices were implanted into the rat striatum 1 week prior to striatal quinolinic acid injections. Animals were evaluated using a battery of validated motor tests, and histology was performed to determine the extent of GDNF diffusion and associated prevention of neuronal cell loss and behavioral deficits. Results. Encapsulated cell-based delivery of GDNF produced widespread distribution of GDNF throughout the entire implanted striatum. Stereological estimates of striatal neuron number and volume of lesion size revealed that GDNF delivery resulted in near complete neuroprotection. Conclusions. Delivery of neurotrophic molecules such as GDNF using encapsulated cells has reached a technological point where clinical evaluation is justified. Because GDNF has been effective in animal models of Parkinson’s disease, stroke, epilepsy, and Huntington’s disease, among other debilitating neurodegenerative diseases, encapsulated cell-based delivery of GDNF might represent one innovative means of slowing the neural degeneration seen in a myriad of currently untreatable neurological diseases.

Advances in cell-laden hydrogels for delivering therapeutics

“…Using a similar approach, Gloriana Therapeutics recently reported that encapsulated cells secreting GDNF reduced both behavioral and electrophysiological seizures as well as epilepsy-related anatomical changes when implanted into the hippocampus of epileptic rats [17]. Similar devices were neuroprotective in an excitotoxic rat model of Huntington's disease [18]. These recent reports not only support the basic concepts of cell encapsulation but also bode well for the use of these technologies in a wide range of human conditions.…”

Microencapsulation for Clinical Applications and Transplantation by Using Different Alginates

“…The development of a delivery strategy is limited due to the blood-brain barrier; however, principle studies in animal models may offer new approaches including gene delivery, cell-based delivery, and also biomaterial drug delivery [61]. In the past year, several in vivo studies have been reported for neurodegenerative diseases [71,[74][75][76]. Galli et al used alginate-poly-L-lysine-alginate (APA) microcapsules and cross-linked the spheres with both Ca 2+ and Ba 2+ .…”

Multipronged Attack of Stem Cell Therapy in Treating the Neurological and Neuropsychiatric Symptoms of Epilepsy

“…Furthermore, utilizing stem cells to deliver these neurotrophic factors may be therapeutically potent in epilepsy. GDNF-releasing ARPE-19 cells were transplanted in quinolinic acid rats, a model of Huntington’s disease ( Emerich et al, 2019 ). Treatment resulted in effective GDNF permeation throughout the rat striatum ( Emerich et al, 2019 ).…”

“…GDNF-releasing ARPE-19 cells were transplanted in quinolinic acid rats, a model of Huntington’s disease ( Emerich et al, 2019 ). Treatment resulted in effective GDNF permeation throughout the rat striatum ( Emerich et al, 2019 ). GDNF ameliorated behavioral impairments and functioned to maintain healthy striatal size ( Emerich et al, 2019 ).…”