Encapsulated living choroid plexus cells: potential long-term treatments for central nervous system disease and trauma

Abstract

In neurodegenerative disease and in acute brain injury, there is often local up-regulation of neurotrophin production close to the site of the lesion. Treatment by direct injection of neurotrophins and growth factors close to these lesion sites has repeatedly been demonstrated to improve recovery. It has therefore been proposed that transplanting viable neurotrophin-producing cells close to the trauma lesion, or site of degenerative disease, might provide a novel means for continuous delivery of these molecules directly to the site of injury or to a degenerative region. The aim of this paper is to summarize recent published information and present new experimental data that indicate that long-lasting therapeutic implants of choroid plexus (CP) neuroepithelium may be used to treat brain disease. CP produces and secretes numerous biologically active neurotrophic factors (NT). New gene microarray and proteomics data presented here indicate that many other anti-oxidant, anti-toxin and neuronal support proteins are also produced and secreted by CP cells. In the healthy brain, these circulate in the cerebrospinal fluid through the brain and spinal cord, maintaining neuronal networks and associated cells. Recent publications describe how transplanted CP cells and tissue, either free or in an immunoprotected encapsulated form, can effectively deliver therapeutic molecules when placed near the lesion or site of degenerative disease in animal models. Using simple techniques, CP neuroepithelial cell clusters in suspension culture were very durable, remaining viable for 6 months or more in vitro. The cell culture conditions had little effect on the wide range and activity of genes expressed and proteins secreted. Recently, completed experiments show that implanting CP within alginate-poly-ornithine capsules effectively protected these xenogeneic cells from the host immune system and allowed their survival for 6 months or more in the brains of rats, causing no adverse effects. Previously reported evidence demonstrated that CP cells support the survival and differentiation of neuronal cells in vitro and effectively treat acute brain injury and disease in rodents and non-human primates in vivo. The accumulated preclinical data together with the long-term survival of implanted encapsulated cells in vivo provide a sound base for the investigation of these treatments for chronic inherited and established neurodegenerative conditions.

Combining Cell-Based Therapies and Neural Prostheses to Promote Neural Survival

“…The choroid plexus was removed, finely dissected, digested with collagenase and allowed to settle before the supernatant was removed and filtered. The preparation was adjusted to approximately 5000 clusters/mL in culture medium before being encapsulated in an alginate membrane using good manufacturing practice techniques previously described [24]. The alginate membrane is biocompatible and semi-permeable, permitting the transfer of secreted NTs, gases, nutrients, and waste products across the membrane and isolating the implanted cells from the immune system of the host [29].…”

“…The choroid plexus produces and secretes a wide range of NTs and other cell survival factors at physiological levels (pg/mL) [24,48]. Significant SGN survival for the NT treatment group was observed in the upper basal cochlear region only (35% greater SGN density compared to the contralateral deafened untreated cochleae), providing evidence that the NTs released by the NTCells were protective for SGNs in this cochlear region.…”

“…The use of cell-based therapies provides a clinically viable NT delivery technique that is less susceptible to adverse side effects than pump-based delivery methods [21][22][23]. In the present study, choroid plexus cells (NTCells, Living Cell Technologies, Auckland, New Zealand), which produce and release a cocktail of NTs [24], were encapsulated in biocompatible alginate and implanted into the neonataldeafened cat cochlea in combination with a cochlear implant electrode array. The results showed that treatment with cellbased NT therapy for an extended duration (as much as 8 months) provided protection of SGNs and their peripheral processes from deafness-induced changes, and also that survival effects were enhanced by concurrent chronic ES via a cochlear implant.…”

Cell Replacement Therapy: The Rationale for Encapsulated Porcine Islet Transplantation

“…However, unlike cells, organs are difficult to screen against potential infectious agents. If clinical trials with cell transplants for diabetes are successful, porcine islet transplants will lead the way for the use of other cells for the treatment of nervous system disorders and enzyme deficiencies (Skinner et al, 2009). Porcine islet xenotransplantation has the potential to be beneficial for those with absolute insulin deficiency.…”

“…The central core containing the islets is liquefied alginate and the outer surface is a membrane formed by ionic interaction between positively charged poly-L-ornithine (or poly-L-lysine) and negatively charged alginate. Properly made, the membrane is remarkably robust (Skinner et al, 2009). Since up to a million capsules may be required for treatment, the production must be reproducible, using durable equipment to Good Manufacturing Practice (GMP) standards.…”