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.
Highlights
Treating neurodegenerative diseases is an urgent challenge
While neurotrophic factors have been consistently effective in animal models [1,2,3,4,5,6,7,8], clinical development and evaluation has been limited
A major reason for the delayed development of effective neurotrophic therapies has been the inability to deliver them across the blood-brain barrier (BBB) directly to target sites in a stable, controlled, and continuous manner [9,10,11,12,13]
Summary
Treating neurodegenerative diseases is an urgent challenge. Neurotrophic factors are attractive therapeutic candidates because they can enhance neuronal functioning, are neuroprotective, and have the potential to reverse ongoing neurodegeneration that causes neurological deficits. While neurotrophic factors have been consistently effective in animal models [1,2,3,4,5,6,7,8], clinical development and evaluation has been limited. Several strategies are under development to optimize the diffusion and spread of trophic factors into the brain tissue. These include direct brain infusion [14], various gene therapy approaches [7, 8], cell therapies [15], and biomaterial-based drug-delivery systems [15]. Each approach has its own advantages and limitations, but none have yet produced significant enough efficacy to justify widespread clinical evaluation
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