RESCUE OF MOTONEURONS FROM AXOTOMY-INDUCED CELL-DEATH BY POLYMER ENCAPSULATED CELLS GENETICALLY-ENGINEERED TO RELEASE CNTF

The neurodegenerative disease amyotrophic lateral sclerosis (ALS) resu lts from the progressive loss of motoneurons, leading to death in a fe w Sears. Ciliary neurotrophic factor (CNTF), which decreases naturally occurring and axotomy-induced cell death, may result in slowing of mo toneuron loss and has been evaluated as a treatment for ALS. Effective administration of this protein to motoneurons may be hampered by the exceedingly short half-life of CNTF, and the inability to deliver effe ctive concentration into the central nervous system after systemic adm inistration in vivo. The constitutive release of CNTF from genetically engineered cells mag represent a solution to this delivery problem. I n this work, baby hamster kidney (BHK) cells stably transfected with a chimeric plasmid construct containing the gene for human or mouse CNT F were encapsulated in polymer fibers, which prevents immune rejection and allow long-term survival of the transplanted cells. In vitro bioa ssays show that the encapsulated transfected cells release bioactive C NTF. In vivo, systemic delivery of human and mouse CNTF from encapsula ted cells was observed to rescue 26 and 27% more facial motoneurons, r espectively, as compared to capsules containing parent BHK cells 1 wk postaxotomy in neonatal rats. With local application of CNTF on the ne rve stump and by systemic delivery through repeated subcutaneous injec tions, 15 and 13% more rescue effects were observed. These data illust rate the potential of using encapsulated genetically engineered cells to continuously release CNTF to slow down motoneuron degeneration foll owing axotomy and suggest that encapsulated cell delivery of neurotrop hic factors mag provide a general method for effective administration of therapeutic proteins for the treatment of neurodegenerative disease s.