Evaluation of an Intrathecal Immune Response in Amyotrophic Lateral Sclerosis Patients Implanted with Encapsulated Genetically Engineered Xenogeneic Cells

Abstract

A phase I/II clinical trial has been performed in 12 amyotrophic lateral sclerosis (ALS) patients to evaluate the safety and tolerability of intrathecal implants of encapsulated genetically engineered baby hamster kidney (BHK) cells releasing human ciliary neurotrophic factor (CNTF). These patients have been assessed for a possible intrathecal or systemic immune response against the implanted xenogeneic cells. Hundreds of pg CNTF/ml could be detected for several weeks in the cerebrospinal fluid (CSF) of 9 out of 12 patients, in 2 patients up to 20 weeks after capsule implantation. Slightly elevated leukocyte counts were observed in 6 patients. Clear evidence for a delayed humoral immune response was found in the CSF of only 3 patients out of 12 (patients #4, #6, and #10). Characterization of the antigen(s) recognized by the antibodies present in these CSF samples allowed to identify bovine fetuin as the main antigenic component. The defined medium used for maintaining the capsules in vitro before implantation contains bovine fetuin. Fetuin may therefore still be adsorbed to the surface of the cells and/or the polymer membrane, or be present in the medium surrounding the encapsulated cells at the time of implantation. Because of the insufficient availability of CSF samples, as well as the relatively poor sensitivity of the assays used, a weak humoral immune response against components of the implanted cells themselves cannot be excluded. However, the present study demonstrates that encapsulated xenogeneic cells implanted intrathecally can survive for up to 20 weeks in the absence of immunosuppression and that neither CNTF nor the presence of antibodies against bovine fetuin elicit any adverse side effects in the implanted patients.

Intracerebroventricular Injection of Encapsulated Human Mesenchymal Cells Producing Glucagon-Like Peptide 1 Prolongs Survival in a Mouse Model of ALS

“…Encapsulation is a promising approach to reduce the risks and complications associated with cellular therapies in the central nervous system: In a first phase I clinical trial in ALS to assess safety and tolerability of encapsulated genetically engineered baby hamster kidney (BHK) cells releasing human ciliary neurotrophic factor (CNTF), therapeutic levels of the secreted peptide could be detected for several weeks without limiting side effects [37]. A phase I/II clinical trial confirmed the safety and tolerability of intrathecal implants of these cell capsules, with signs of only a very mild humoral immune response [38]. Studies in experimental animal models using the same cell capsules as in the present study showed complete prevention of any immune response by microencapsulation of cells prior to transplantation [21], [24].…”

Cell encapsulation: technical and clinical advances

“…Cell encapsulation overcomes these issues by delivering therapeutic molecules directly to the brain area of interest (Box 1). Initial clinical trials for amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) [68][69][70] were based on solid preclinical data showing that encapsulated cells could be configured into implantable capsules that were biocompatible, maintained cell viability for extended periods of time, and were functional in animal models. However, during Phase I clinical trials, it became evident that obstacles remained.…”

Injectable Hydrogels Providing Sustained Delivery of Vascular Endothelial Growth Factor are Neuroprotective in a Rat Model of Huntington’s Disease

“…This system, in the current iteration which provides sustained release of VEGF for 2-3 weeks, though would likely not provide delivery long enough to justify its clinical use in a chronic disease such as HD. Still, several approaches are being evaluated both pre-clinically and clinically that might be suitable for delivery of VEGF or other molecules on the order of years to the CNS (Zurn et al 2000;Bloch et al 2004;Yasuhara and Date 2007;Marks et al 2008). The angiogenic effects of VEGF have been well documented, but its role in neuroprotection is becoming increasingly clear.…”