Article: article from journal or magazin.
Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients.
Publication types: Clinical Trial ; Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Neuronal growth factors hold promise for providing therapeutic benefits in various neurological disorders. As a means of ensuring adequate central nervous system delivery of growth factors and minimizing significant adverse side effects associated with systemic delivery methods, we have developed an ex vivo gene therapy approach for protein delivery using encapsulated genetically modified xenogeneic cells. Ciliary neurotrophic factor (CNTF) has been shown in various rodent models to reduce the motor neuron cell death similar to that seen in amyotrophic lateral sclerosis (ALS). The initial trials focusing on the systemic administration of CNTF for ALS have been discontinued as a result of major side effects, thus preventing determination of the potential efficacy of the molecule. In order to deliver CNTF directly to the nervous system, we conducted a phase I study in which six ALS patients were implanted with polymer capsules containing genetically engineered baby hamster kidney cells releasing approximately 0.5 microgram of human CNTF per day in vitro. The CNTF-releasing implants were surgically placed 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 implantation. Intrathecal delivery of CNTF was not associated with the limiting side effects observed with systemic delivery. These results demonstrate that neurotrophic factors can be continuously delivered within the CSF of humans by an ex vivo gene therapy approach, opening new avenues for the treatment of neurological diseases.
Amyotrophic Lateral Sclerosis/drug therapy, Amyotrophic Lateral Sclerosis/genetics, Animals, Cell Transplantation/methods, Ciliary Neurotrophic Factor, Cricetinae, Drug Implants/administration & dosage, Drug Implants/chemistry, Genetic Therapy/methods, Genetic Vectors/chemistry, Genetic Vectors/genetics, Humans, Injections, Spinal, Kidney/cytology, Kidney/physiology, Lumbar Vertebrae/surgery, Nerve Tissue Proteins/administration & dosage, Nerve Tissue Proteins/cerebrospinal fluid, Recombinant Proteins/administration & dosage, Recombinant Proteins/biosynthesis
Web of science
Last modification date