Intrathecal delivery of CNTF using encapsulated genetically modifiedxenogeneic cells in amyotrophic lateral sclerosis patients

Abstract

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.

Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia

“…[25][26][27] Cell encapsulation has also been employed to locally administer neurotrophic factors (CNTF and GDNF) locally in the central nervous system, both in pre-clinical and clinical studies, for the treatment of neurodegenerative disorders. [28][29][30] During reconstructive surgery, skin flaps are employed to cover wounds with poorly vascularized recipient beds where the damage is too extensive to permit repair using a skin graft. A skin flap is comprised of skin and subcutaneous tissue that is transferred from one area of the body to another, while maintaining an attachment to the body (vascular pedicle) for nourishment.…”

Bcl-2 expression by retrograde transport of adenoviral vectors with Cre-loxP recombination system in motor neurons of mutant SOD1 transgenic mice

“…Some of these have been tested in therapeutic trials. In their investigation of gene-therapeutic modalities for motor neuron diseases, Aebischer et al 8 used encapsulated, genetically modified xenogeneic cells to deliver ciliary neurotrophic factor (CNTF) intrathecally into patients with ALS. Haase et al 9 demonstrated that adenovirus-mediated gene transfer of neurotrophin-3 (NT-3) or NT-3 and CNTF could produce substantial therapeutic effects in pmn (progressive motor neuropathy) mutant mice after intramuscular injection of the NT-3 or NT-3 and CNTF adenoviral vectors.…”

Double-copy bicistronic retroviral vector platform for gene therapy and tissue engineering: application to melanoma vaccine development

“…Besides cancer vaccines, it is envisioned that this particular design may have utility in tissue engineerhCMV-IE promoter-containing DCCMV vector, which combines the principles of double-copy and IRES vector ing applications where the intent is to implant polymer encapsulated cell lines genetically engineered to continudesigns, 21,35 reproducibly directed high stable levels of exogenous gene expression in a panel of four human ously secrete pharmacological levels of bioactive proteins. 43,44 For such applications, it may be advantageous melanoma cell lines.…”