INTRATHECAL DELIVERY OF CNTF USING ENCAPSULATED GENETICALLY-MODIFIED XENOGENEIC CELLS IN AMYOTROPHIC-LATERAL-SCLEROSIS PATIENTS

Neuronal growth factors hold promise for providing therapeutic benefit s in various neurological disorders. As a means of ensuring adequate c entral nervous system delivery of growth factors and minimizing signif icant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein deliver y using encapsulated genetically modified xenogeneic cells. Ciliary ne urotrophic factor (CNTF) has been shown in various rodent models to re duce the motor neuron cell death similar to that seen in amyotrophic l ateral sclerosis (ALS)(1-3). The initial trials focusing on the system ic administration of CNTF for ALS have been discontinued as a result o f major side effects, thus preventing determination of the potential e fficacy of the molecule(4,5). In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which six ALS patient s were implanted with polymer capsules containing genetically engineer ed baby hamster kidney cells releasing approximately 0.5 mu g of human CNTF per day in vitro. The CNTF-releasing implants were surgically pl aced within the lumbar intrathecal space. Nanogram levels of CNTF were measured within the patients' cerebrospinal fluid (CSF) for at least 17 weeks post-transplantation, whereas it was undetectable before impl antation. Intrathecal delivery of CNTF was not associated with the lim iting side effects observed with systemic delivery. These results demo nstrate that neurotrophic factors can be continuously delivered within the CSF of humans by an ex vivo gene therapy approach, opening new av enues for the treatment of neurological diseases.