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Invited Commentary: Treatment of Diseases of the Central Nervous System Using Encapsulated Cells, by A. F. Hottinger and P. Aebischer (Advances and Technical Standards in Neurosurgery Vol. 25)
Abstract
The treatment of neurological disorders with conventional drug therapies, such as L-dopa for Parkinson’s disease, has traditionally been achieved by the administration of the drugs through peripheral routes. However, this approach is hampered by the problem of drug penetration across the blood brain barrier, as well as being relatively non-specific with respect to site of action within the CNS. The discovery of high molecular weight proteins which can affect the development of the CNS and protect against various types of neuronal cell death, has stimulated efforts to explore their use as neuroprotective agents in a variety of pathological conditions [3]. The direct delivery of these large peptides to the CNS can be achieved either by injection through an intracerebral cannula, which then communicates to the outside world, or by implantation of a closed system which has the capacity to continuously release the neuroactive substance. The advantages of an implantable system over pump injection are outlined by the authors and relate largely to practical issues such as the risk of infection associated with an indwelling cannula. Two main approaches have been employed in the development of implantable devices.
Spinal dural arteriovenous fistula (SDAVF) is a rare disease, the etiology of which is not entirely clear. It is the most common vascular malformation of the spinal cord, comprising 60–80 % of the cases. The clinical presentation and imaging findings may be nonspecific and misleading, often mistaking it for other entities like demyelinating or degenerative diseases of the spine.
This chapter describes the imaging findings, clinical signs, and symptoms of this disease and also the available treatment options according to the current literature.
Angiography is still considered the gold standard for diagnosis; however, MRI/MRA is increasingly used as a screening tool. Modern endovascular techniques are becoming increasingly more effective in treating SDAVF offering a less invasive treatment option; however, they still lag behind surgical success rates which approach 100 %. The outcome of both treatment options is similar if complete obliteration of the fistula is obtained and depends mainly on the severity of neurological dysfunction before treatment.
Heightened awareness by radiologists and clinicians to this rare entity is essential to make a timely diagnosis of this treatable disease. A multidisciplinary treatment approach is required in order to make appropriate treatment decisions.
Publisher Summary This chapter describes some of the biological properties of the neurotrophins, especially in relation to their specificity for a family of neurotrophin receptors, the trk family of receptor tyrosine kinases. The biology of neurotrophic factors was restricted to the concepts that arose from the study of nerve growth factor (NGF). The neurotrophin family currently compromises four members. At the level of the amino acid sequence of the mature proteins, there is 50–60% identity between any two members of this family. The neurotrophins are highly basic proteins of around 120 amino acids in length and each is processed from a larger precursor. The three disulphide bridges that were originally identified in the structure of NGF appear to be retained in each of the neurotrophins and each of the six contributing cystine residues is flanked by regions of high homology. Detailed study of the biological properties of this protein has served as the model with which to test various hypotheses on the role of neurotrophic factors in development and maintenance of peripheral (PNS) and central nervous system (CNS) neurons.
Alzheimer's disease involves substantial cholinergic cell deficits; other neurodegenerative diseases involve similar losses of certain cell populations. Optimal therapies may involve tissue replacement coupled with the controlled delivery of appropriate growth factors, such as nerve growth factor, to the graft site. In this review article we describe the kinetics of protein release from three modes of controlled protein delivery to transplants: delivery from a polymer matrix, delivery form polymeric microspheres, and delivery from genetically engineered cells. The efficacy and feasibility of each of these delivery strategies for potential treatment of patients diagnosed with neurodegenerative disorders is discussed.
The long-term delivery of growth factors and other proteins into the CNS at putatively therapeutic yet safe levels continues to be technically constrained. In the present studies, the gene encoding human nerve growth factor (hNGF), introduced into a dihydrofolate reductase-based pNUT expression vector system, was engineered into a clonal baby hamster kidney (BHK) cell line. BHK-hNGF23 and mock-transfected cells were encapsulated in an immunoisolating polymeric device and transplanted into the lateral ventricles of healthy young adult rats for 13.5 months. As measured by ELISA, nanogram quantities of hNGF were released by encapsulated cells both prior to implantation (3.6 +/- 0.8 ng/device/24 h) and upon removal from rat lateral ventricles after 13.5 months in vivo (2.2 +/- 0.4 ng/ device/24 h). In addition, the hNGF released into the tissue culture medium was biologically active. Long-term encapsulated cell survival was confirmed by histologic analysis. The presence of genomic DNAs (hNGF transgene), as determined by PCR analyses, revealed that the transgene copy number from the recovered BHK-hNGF23 cells after 13.5 months in vivo was equivalent to preimplant levels. No deleterious effects from hNGF were detectable on body weight, mortality rate, motor/ambulatory function, or cognitive function as assessed with the Morris water maze and delayed matching to position in healthy young adult rats. In addition, there was no evidence that hNGF from these encapsulated cells produced hyperalgesia. Only tests of somatosensory thresholds revealed statistically significant effects related to the hNGF delivered in the present study, and that effect was limited to a decrease in the number of trials to asymptote. Animals receiving BHK-hNGF23 implants exhibited a marked hypertrophy of cholinergic neurons within the striatum (22% increase) and nucleus basalis (7% increase) but not the medial septum ipsilateral to the capsule. Moreover a robust sprouting of cholinergic fibers was observed within the frontal cortex and lateral septum proximal to the implant. These results indicate that encapsulated xenogeneic cells provide a safe and effective method for the long-term delivery of hNGF and potentially other neurotrophic factors within the CNS.
Two groups of rats with unilateral 6OHDA lesions received either intrastriatal suspension grafts of embryonic ventral mesencephalon or sham grafts. Three subgroups of each of these received intrastriatal infusions of 1000 ng or 500 ng glial cell-line derived trophic factor (GDNF) or vehicle alone for 10 consecutive days. There was a highly significant dose-dependent effect of GDNF both on the number of TH-positive cells surviving in the grafts and on the density of fibre outgrowth. All grafted rats showed rapid compensation of amphetamine-induced rotation compared with rats with sham grafts. GDNF may provide a powerful tool to enhance the survival and maturation of dopaminergic neurones within mesencephalic transplants.
Huntington's disease is a genetic disorder that results from degeneration of striatal neurons, particularly those containing GABA (gamma-aminobutyric acid). There is no effective treatment for preventing or slowing this neuronal degeneration. Ciliary neurotrophic factor (CNTF) is a trophic factor for striatal neurons and therefore a potential therapeutic agent for Huntington's disease. Here we evaluate CNTF as a neuroprotective agent in a nonhuman primate model of Huntington's disease. We gave cynomolgus monkeys intrastriatal implants of polymer-encapsulated baby hamster kidney fibroblasts that had been genetically modified to secrete human CNTF. One week later, monkeys received unilateral injections of quinolinic acid into the previously implanted striatum to reproduce the neuropathology seen in Huntington's disease. Human CNTF was found to exert a neuroprotective effect on several populations of striatal cells, including GABAergic, cholinergic and diaphorase-positive neurons which were all destined to die following administration of quinolinic acid. Human CNTF also prevented the retrograde atrophy of layer V neurons in motor cortex and exerted a significant protective effect on the GABAergic innervation of the two important target fields of the striatal output neurons (the globus pallidus and pars reticulata of the substantia nigra). Our results show that human CNTF has a trophic influence on degenerating striatal neurons as well as on critical non-striatal regions such as the cerebral cortex, supporting the idea that human CNTF may help to prevent the degeneration of vulnerable striatal populations and cortical-striatal basal ganglia circuits in Huntington's disease.
The transplantation of genetically modified cells represents one potential means of delivering trophic factors to the brain to support the survival of host neurons and to increase the survival of co-grafted cells. The present study examined the ability of encapsulated baby hamster kidney (BHK) fibroblasts, which were genetically modified to produce human nerve growth factor (hNGF), to provide long-term trophic support to co-grafted adrenal chromaffin cells. Following polymer encapsulation, BHK-hNGF cells were grafted into the striatum of hemiparkinsonian rats together with unencapsulated adrenal medullary chromaffin cells. Secretion of hNGF from the encapsulated cells, morphology of these cells, apomorphine-induced rotational behavior of the host animals, and survival of the co-grafted chromaffin cells were examined 1, 6, and 12 months after transplantation. Analysis of retrieved capsules revealed that the BHK cells survived and continued to release hNGF at a level of 2-3 ng/day even 12 months after transplantation. Although the animals receiving adrenal medulla alone did not show recovery of apomorphine-induced rotational behavior, the animals receiving adrenal medulla intrastriatal hNGF-secreting cells showed a significant decrease (40-50%) in apomorphine-induced rotation within 1 month postimplantation that remained stable for the 12-month test period. Tyrosine hydroxylase immunocytochemistry further revealed that while survival of chromaffin cells without hNGF support was poor, co-grafting of adrenal medulla and BHK-hNGF cells dramatically 926- to 32-fold) increased chromaffin cell survival 1, 6, and 12 months after transplantation. These results demonstrate that (1) encapsulated BHK cells survive for extended periods of time in vivo while continuing to secrete hNGF, (2) the continued secretion of hNGF provides trophic support for co-grafted adrenal chromaffin cells, and (3) the increased chromaffin cell survival is associated with long-term, stable behavioral recovery. These data further support the potential use of this approach for treating Parkinson's disease.
Encapsulated CNTF-producing fibroblasts reverse motor and cognitive deficits and protect striatal neurons in a chronic primate model of Huntington’s disease
- V Mittoux
- Jm Joseph
- F Condé
- S Palfi
- A Zum
- C Dautry
- T Poyot
- M Peschanski
- P Aebischer
- P Hantraye
Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease
- Df Emerich
- Sr Winn
- Pm Hantraye
- M Peschanski
- Ey Chen
- Y Chu
- P Mcdermott
- Ee Baetge
- Jh Kordower