Abstract
The use of neuroactive substances as therapeutic agents represents a major focus of today’s neurobiology. The delivery of these substances to the CNS is however complicated by several factors including low oral and trans-dermal availability and short half-lives (Battler et al. 1993). The blood brain barrier (BBB) further prevents the passage of most molecules from the circulation to the brain tissue (Poduslo and Curran 1996). To reach the CNS, these molecules have therefore to be directly injected into the brain with an adequate delivery system, such as a pump. This method is however of limited use for long term applications due to the instability of the therapeutic molecules (Penn et al. 1997) and the risk of infection linked to the need for repeated refilling. Implantation of cells that have been genetically modified to release therapeutic molecules represents an alternative that can circumvent the above mentioned limitations. The cells can be implanted in specific targets allowing the localized continuous release of bioactive molecules. This approach has been used successfully in various models of neurodegenerative diseases. This technique is however limited by the immune rejection in case of non autologous sources and potential tumor formation with the use of cell lines (Jaeger 1985) preventing clinical applications. One solution to these problems is the technology of encapsulation. The transplanted cells are surrounded by a selectively permeable biocompatible membrane, preventing the dissemination of the cells as well as immune rejection.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Aebischer P, Buchser E, Joseph JM, Favre J, de Tribolet N, Lysaght M, Rudnick S, Goddard M (1994) Transplantation in humans of encapsulated xenogeneic cells without immunosuppression. A preliminary report. Transplantation 58: 1275–1277
Aebischer P, Goddard M, Tresco PA (1993) Cell encapsulation for the nervous system. In: Goosen MFA (ed) Fundamentals of animal cell encapsulation and immobilization. Boca Raton, Florida, pp 197–220
Aebischer P, Lysaght MJ (1995) Immunoisolation and cellular transplantation. Xeno 3: 43–48
Aebischer P, Pochon NA, Heyd B, Deglon N, Joseph JM, Zurn AD, Baetge EE, Hammang JP, Goddard M, Lysaght M, Kaplon F, Kajo AC, Schluepp M, Hirt L, Regli F, Porchet F, de Tribolet N (1996) Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF. Hum Gene Ther 7: 851–860
Aebischer P, Tresco PA, Winn SR, Greene LA, Jaeger CB (1991) Long-term cross-species brain transplantation of a polymer-encapsulated dopamine-secreting cell line. Exp Neurol 111: 269–275
ALS CNTF treatment study (ACTS) Study group (1996) A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 46: 1244–1249
Andres PL, Hedlund W, Finison L, Conlon T, Felmus M, Munsat TL (1986) Quantitative motor assessment in amyotrophic lateral sclerosis. Neurology 36: 937–941
Battler A, Scheinowitz M, Bor A, Hasdai D, Vered Z, Di Segni E, Varda-Bloom N, Nass D, Engelberg S, Eldar M (1993) Intracoronary injection of basic fibroblast growth factor enhances angiogenesis in infarcted swine myocardium. J Am Coll Cardiol 22: 2001–2006
Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33: 87–107
Bjorklund A, Stenevi U, Dunnett SB, Gage FH (1982) Cross-species neural grafting in a rat model of Parkinson’s disease. Nature 298: 652–654
Blomer U, Naldini L, Verma IM, Trono D, Gage FH (1996) Applications of gene therapy to the CNS. Hum Mol Genet 5: 1397–1404
Brundin P, Nilsson OG, Strecker RE, Lindvall O, Astedt B, Bjorklund A (1986) Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson’s disease. Exp Brain Res 65: 235–240
Buchser E, Goddard M, Heyd B, Joseph JM, Favre J, de Tribolet N, Lysaght M, Aebischer P (1996) Immunoisolated xenogenic chromaffin cell therapy for chronic pain. Initial clinical experience. Anesthesiology 85: 1005–1012
Curtis R, Adryan KM, Zhu Y, Harkness PJ, Lindsay RM, DiStefano PS (1993) Retrograde axonal transport of ciliary neurotrophic factor is increased by peripheral nerve injury. Nature 365: 253–255
Curtis R, Scherer SS, Somogyi R, Adryan KM, Ip NY, Zhu Y, Lindsay RM, DiStefano PS (1994) Retrograde axonal transport of LIF is increased by peripheral nerve injury: correlation with increased LIF expression in distal nerve. Neuron 12: 191–204
Décosterd I, Buchser E, Gilliard N, Saydoff J, Zum AD, Aebischer P (1998) Intrathecal implants of bovine chromaffin cells alleviate mechano-allodynia in a rat model of neuropathic pain. Pain (in press)
Emerich DF, Lindner MD, Winn SR, Chen EY, Frydel BR, Kordower JH (1996) Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington’s disease. Neuroscience 16: 5168–5181
Emerich DF, Winn SR, Hantraye PM, Peschanski M, Chen EY, Chu YP, McDermott P, Baetge EE, Kordower JH (1997) Protective effect of encapsulated cells producing neurotrophic factor Cntf in a monkey model of huntingtons disease. Nature 386: 395–399
Fantuzzi G, Benigni F, Sironi M, Conni M, Carelli M, Cantoni L, Shapiro L, Dinarello CA, Sipe JD, Ghezzi P (1995) Ciliary neurotrophic factor (CNTF) induces serum amyloid A, hypoglycaemia and anorexia, and potentiates IL-1 induced corticosterone and IL-6 production in mice. Cytokine 7: 150–156
Freed WJ, Poltorak M, Becker JB (1990) Intracerebral adrenal medulla grafts: a review. Exp Neurol 110: 139–166
Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20: 269–287
Ginzburg R, Seltzer Z (1990) Subarachnoid spinal cord transplantation of adrenal medulla suppresses chronic neuropathic pain behavior in rats. Brain Res 523: 147–150
Gusella JF, MacDonald ME (1995) Huntington’s disease. Cell Biology 6:21–28
Hama AT, Pappas GD, Sagen J (1996) Adrenal medullary implants reduce transsynaptic degeneration in the spinal cord of rats following chronic constriction nerve injury. Exp Neurol 137: 81–93
Hama AT, Sagen J (1993) Reduced pain-related behavior by adrenal medullary transplants in rats with experimental painful peripheral neuropathy. Pain 52: 223–231
Hama AT, Sagen J (1994) Alleviation of neuropathic pain symptoms by xenogeneic chromaffin cell grafts in the spinal subarachnoid space. Brain Res 651: 183–193
Hart DN, Fabre JW (1981) Demonstration and characterization of la-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med 154: 347–361
Horellou P, Lundberg C, Le Bourdelles B, Wictorin K, Brundin P, Kaien P, Bjorklund A, Mallet J (1991) Behavioural effects of genetically engineered cells releasing dopa and dopamine after intracerebral grafting in a rat model of Parkinson’s disease. J Physiol 85: 158–170
Horellou P, Mallet J (1997) Gene therapy for Parkinsons disease. Mol Neurobiol 15: 241–256
Jaeger CB (1985) Immunocytochemical study of PC12 cells grafted to the brain of immature rats. Exp Brain Res 59: 615–624
Joseph JM, Goddard MB, Mills J, Padrun V, Zurn A, Zielinski B, Favre J, Gardaz JP, Mosimann F, Sagen J, Christenson L, Aebischer P (1994) Transplantation of encapsulated bovine chromaffin cells in the sheep subarachnoid space: a preclinical study for the treatment of cancer pain. Cell Transplant 3: 355–364
Kordower JH, Fiandaca MS, Notter MF, Hansen JT, Gash DM (1990) NGF-like trophic support from peripheral nerve for grafted rhesus adrenal chromaffin cells. J Neurosurg 73: 418–428
Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237: 1154–1162
Lim F, Sun AM (1980) Microencapsulated islets as bioartificial endocrine pancreas. Science 210: 908–910
Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260: 1130–1132
Livett BG, Dean DM, Whelan LG, Udenfriend S, Rossier J (1981) Co-release of enkephalin and catecholamines from cultured adrenal chromaffin cells. Nature 289: 317–319
Meyer M, Matsuoka I, Wetmore C, Olson L, Thoenen H (1992) Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J Cell Biol 119: 45–54
Miller RG, Bryan WW, Dietz MA, Munsat TL, Petajan JH, Smith SA, Goodpasture JC (1996a) Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis. Neurology 47: 1329–1331
Miller RG, Petajan JH, Bryan WW, Armon C, Barohn RJ, Goodpasture JC, Hoagland RJ, Parry GJ, Ross MA, Stromatt SC (1996b) A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann Neurol 39: 256–260
Mitsumoto H, Ikeda K, Klinkosz B, Cedarbaum JM, Wong V, Lindsay RM (1994) Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 265: 1107–1110
Mittoux V, Joseph JM, Palfi S, Condé F, Zurn AD, Dautry C, Peschanski M, Aebischer P, Hantraye P (1998) Neuroprotective and behavioral effects of encapsulated CNTF-producing fibroblasts in a chronic primate model of Huntington’s disease. In: CNTF and associates: from gene to therapy. Paris, pp 52–54
Norris FH, Jr., Calanchini PR, Fallat RJ, Panchari S, Jewett B (1974) The administration of guanidine in amyotrophic lateral sclerosis. Neurology 24: 721–728
Ortega JD, Sagen J, Pappas GD (1992) Short-term immunosuppression enhances long-term survival of bovine chromaffin cell xenografts in rat CNS. Cell Transplant 1: 33–41
Ossipov MH, Lopez Y, Bian D, Nichols ML, Porreca F (1997) Synergistic antinociceptive interactions of morphine and clonidine in rats with nerve-ligation injury. Anesthesiology 86: 196–204
Palfi S, Joseph J-M, Condé F, Braguglia D, Mittoux V, Zurn AD, Riche D, Peschanski M, Aebischer P, Hantraye P (1998) Transplantation of polymer encapsulated GDNF-secreting xenogeneic cells leads to prolonged functional recovery in late stage parkinsonian baboons (submitted)
Penn RD, Kroin JS, York MM, Cedarbaum JM (1997) Intrathecal ciliary neurotrophic factor delivery for treatment of amyotrophic lateral sclerosis (phase I trial). Neurosurgery 40: 94–99
Poduslo JF, Curran GL (1996) Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain research. Mol Brain Res 36: 280–286
Pollard HB, Pazoles CJ, Creutz CE, Scott JH, Zinder O, Hotchkiss A (1984) An osmotic mechanism for exocytosis from dissociated chromamn cells. J Biol Chem 259: 1114–1121
Portenoy RK (1993) Cancer pain management. Semin Oncol 20: 19–35
Puntillo K, Casella V, Reid M (1997) Opioid and benzodiazepine tolerance and dependence: application of theory to critical care practice. Heart Lung 26: 317–324
Sagen J, Pappas GD, Perlow MJ (1986a) Adrenal medullary tissue transplants in the rat spinal cord reduce pain sensitivity. Brain Res 384: 189–194
Sagen J, Pappas GD, Pollard HB (1986b) Analgesia induced by isolated bovine chromaffin cells implanted in rat spinal cord. Proc Natl Acad Sci USA 83: 7522–7526
Sagen J, Wang H, Hama AT, Pappas GD (1995) Adrenal chromaffin cells: preparation and use in pain models. In: Ricordi C (ed) Austin, Landes
Sagen J, Wang H, Tresco PA, Aebischer P (1993) Transplants of immuno-logically isolated xenogeneic chromaffin cells provide a long-term source of pain-reducing neuroactive substances. J Neurosci 13: 2415–2423
Sagot Y, Tan SA, Baetge E, Schmalbruch H, Kato AC, Aebischer P (1995) Polymer encapsulated cell lines genetically engineered to release ciliary neuro-trophic factor can slow down progressive motor neuronopathy in the mouse. Eur J Neurosci 7: 1313–1322
Sambrook T, Fritsch EF, Maniatis T (1989) Molecular cloning. In: Harbor CS (ed) A laboratory manual. New York
Schueler SB, Sagen J, Pappas GD, Kordower JH (1995) Long-term viability of isolated bovine adrenal medullary chromaffin cells following intrastriatal transplantation. Cell Transplant 4: 55–64
Sendtner M, Holtmann B, Kolbeck R, Thoenen H, Barde YA (1992a) Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. Nature 360: 757–759
Sendtner M, Kreutzberg GW, Thoenen H (1990) Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature 345:440–441
Sendtner M, Schmalbruch H, Stockli KA, Carroll P, Kreutzberg GW, Thoenen H (1992b) Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathy. Nature 358: 502–504
Siuciak JA, Altar CA, Wiegand SJ, Lindsay RM (1994) Antinociceptive effect of brain-derived neurotrophic factor and neurotrophin-3. Brain Res 633: 326–330
Sloan DJ, Wood MJ, Charlton HM (1991) The immune response to intra-cerebral neural grafts. Trends Neurosci 14: 341–346
Snider WD, Johnson EM Jr (1989) Neurotrophic molecules. Ann Neurol 26: 489–506
Tandan R, Bradley WG (1985a) Amyotrophic lateral sclerosis: part 1. Clinical features, pathology, and ethical issues in management. Ann Neurol 18: 271–280
Tandan R, Bradley WG (1985b) Amyotrophic lateral sclerosis: part 2. Etiopathogenesis. Ann Neurol 18: 419–431
The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72: 971–983
Tseng JL, Baetge EE, Zurn AD, Aebischer P (1997) Gdnf reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine. J Neurosci 17: 325–333
Uchida K, Takamatsu K, Kaneda N, Toya S, Tsukada Y, Kurosawa Y, Fujita K, Nagatsu T, Kohsaka S (1989) Synthesis of L-3,4-dihydroxyphenylalanine by tyrosine hydroxylase cDNA-transfected C6 cells: application for intracerebral grafting. J Neurochem 53: 728–732
Unsicker K (1993) The trophic cocktail made by adrenal chromaffin cells. Exp Neurol 123: 167–173
Unsicker K, Krieglstein K (1996) Growth factors in chromaffin cells. Prog Neurobiol 48: 307–324
Vaquero J, Arias A, Oya S, Zurita M (1991) Chromamn allografts into arachnoid of spinal cord reduce basal pain responses in rats. Neuroreport 2: 149–151
Verhofstad AA, Coupland RE, Colenbrander B (1989) Immunohistochemical and biochemical analysis of the development of the noradrenaline-and adrenaline-storing cells in the adrenal medulla of the rat and pig. Arch Histol Cytol 52: 351–360
Widner H, Brundin P (1988) Immunological aspects of grafting in the mammalian central nervous system. A review and speculative synthesis. Brain Res 472: 287–324
Winn SR, Tresco PA, Zielinski B, Greene LA, Jaeger CB, Aebischer P (1991) Behavioral recovery following intrastriatal implantation of microencapsulated PC 12 cells. Exp Neurol 113: 322–329
Winnie AP, Pappas GD, Das Gupta TK, Wang H, Ortega JD, Sagen J (1993) Subarachnoid adrenal medullary transplants for terminal cancer pain. A report of preliminary studies. Anesthesiology 79: 644–653
Yaksh TL, Reddy SV (1981) Studies in the primate on the analgetic effects associated with intrathecal actions of opiates, alpha-adrenergic agonists and baclofen. Anesthesiology 54: 451–467
Yan Q, Elliott J, Snider WD (1992) Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 360: 753–755
Yan Q, Matheson C, Lopez OT (1995) In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. Nature 373: 341–344
Yu W, Hao JX, Xu XJ, Saydoff J, Haegerstrand A, Hokfelt T, Wiesenfeldhallin Z (1998) Long-term alleviation of allodynia-like behaviors by intrathecal implantation of bovine chromamn cells in rats with spinal cord injury. Pain 74: 115–122
Zielinski BA, Aebischer P (1994) Chitosan as a matrix for mammalian cell encapsulation. Biomaterials 15: 1049–1056
Zurn AD, Baetge EE, Hammang JP, Tan SA, Aebischer P (1994) Glial cell line-derived neurotrophic factor (GDNF), a new neurotrophic factor for motoneurones. Neuroreport 6: 113–118
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer-Verlag Wien
About this chapter
Cite this chapter
Hottinger, A.F., Aebischer, P. (1999). Treatment of Diseases of the Central Nervous System Using Encapsulated Cells. In: Cohadon, F., et al. Advances and Technical Standards in Neurosurgery. Advances and Technical Standards in Neurosurgery, vol 25. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6412-9_1
Download citation
DOI: https://doi.org/10.1007/978-3-7091-6412-9_1
Publisher Name: Springer, Vienna
Print ISBN: 978-3-7091-7318-3
Online ISBN: 978-3-7091-6412-9
eBook Packages: Springer Book Archive