Neurosurgery

5. Department Neurosurgery

Prof. J.J. Mooy, prof. M.J. Staal

a. Background of research group

- One of the research lines within the department of Neurosurgery concerns the development of new treatment strategies for Parkinson’s disease. Cell therapy as an experimental treatment for Parkinson’s disease has been widely applied since the eighties. Cellular transplantation aims at repairing the defect in the nigro-striatal system. To date two celltypes have been used for this purpose: mesencephalic cells either derived from human or from porcine fetal tissue. A few hundred-transplant procedures have been carried out using human fetal tissue, whereas porcine fetal cell suspensions were transplanted in 12 Parkinson's disease patients. Both methods have their specific drawback. The use of human fetal tissue is restricted by ethical and practical factors. The availability of human abortion tissue is limited and overall too short to be used on large scale. Porcine fetal tissue is associated with the risk of immune intolerance and zoönotic transfection, e.g. porcine endogenous retrovirus (PERV). The department of Neurosurgery has been involved in research concerning the feasibility of the cell transplantation therapy described above. Human fetal dopaminergic tissue prepared after dissection out of the fetal ventral mesencephalon was characterised. Parameters of characterisation were the proportion of neural cells in cell culture, the presence of catecholamines, and the functional effects after transplantation of the dopaminergic cell suspension in the striatum of 6-OHDA lesioned rats and survival and ingrowth in this host striatum. Human fetal tissue appeared to be not a useful source since its availability within the frame of consent was rather limited (1). Porcine fetal tissue has been object of experimental research as well (2-5). Results of a study about the immunological aspects of fetal porcine xenografting will be described soon in a thesis to be completed by a "AGIKO" of the neurosurgical department.

- Another reserach area within the department of Neurosurgery is Neurooncology. With novel advanced techniques (MRI, MRSI, PET) research on experimental as well as clinical aspects of braintumors, such as meningeomas, Schwannomas, hypofyse adenomas, pilocytaire astrocytoma is done. New therapeutical strategies are investigated such as gene therapy, multimodal chemotherapy and conformal radiotherapy. In collaboration with the department of Immunology research is performed on the feasibility of the application of immunotoxins. Stem cell research will be included in neurooncology for elucidating mechanisms in the development of brain tumors, in the repair of neural tissue, damaged by the tumor or its treatment and by using the proven capacity of neural stem cells for migration through the brain in making them therapeutic messengers.

b. Aims

The ultimate aim in restorative stem cell research for Parkinson’s disease is to develop standard procedures to obtain stable, functional dopaminergic neurons from autologous bone marrow for intrastriatal implantation in Parkinson patients. Apparently this is still a long pathway and most of the focus of research will be placed on several intermediate goals.

As far as application of neural stem cells in neuro-oncoloy is concerned, it is aimed to obtain insight in the mechanisms underlying the migratory behaviour of neural stem cells, in order to understand the migratory behaviour of various neural tumor cell and to assess the possibility to use neural stem cells as therapeutical messengers

c. Present and future projects

Restorative stem cell research

The contribution of the department of Neurosurgery in the ongoing stem cell research activities in Groningen has been originally the foundation of the Groningen stem cell cluster. The department has put forward the request of the production of dopaminergic cells not deriving from fetal tissue, for neuroregeneration therapy in Parkinson’s disease. It is obvious that the preclinical research (selection of the optimal stem cell source, isolation and differentiation of neural dopaminergic cells) should be carried out in the laboratories carrying the expertise to achieve this. The specific role in the characterization process of stem cell derived dopaminergic cells will be to implant these cells into the striatum of 6-OHDA lesioned rats and to study behavioral and histological effects, according to previous experience.

Moreover the department of Neurosurgery, in cooperation with the department of Pathology, is able to deliver subventricular zone tissue specimen prepared during autopsy of deceased patients, for the study of adult brain as a potential source of stem cells.

The interest of the departments of Neurology and Neurosurgery for stem cells primarily concerns neuroregenerative therapy for Parkinson’s disease. However differentiation of stem cells into other specific neural cells would potentially open the way for various applications of neural tissue repair therapy like cerebral ischaemic conditions, multiple sclerosis, spinal cord injury and other neurodegenerative diseases different from Parkinson’s disease. Also for these future applications the collaboration between the 2 clinical departments provides a solid base for launching phase I/II clinical trials.

Elucidation of neuro-oncological mechanisms.

One of the main characteristics of malignant brain gliomas that make them resistant to definite therapy up till now is their infiltrative capacity and hence the spread of already malignant cells in apparently healthy brain tissue. Neural stem or progenitor cells have high migratory capacity. Elucidating the underlying mechanisms may help in understanding and counteracting tumor cell infiltration. Glioma cells are supposed to be derived from damaged progenitor cells. Investigations in mechanisms of the role of stem cells in tumor formation seem therefore necessary and appropriate.

- Stem cells as therapeutic messengers. The lack of success of gene therapy for brain tumors up till now is the result of inefficient delivery and transfection of the chosen genetic material by the vectors used so far. Neural stem/progenitor cells have been found to travel along white matter like neoplastic cells, and to be attracted to glial tumor cells even at long distances. Hence, neural stem cells engineered for one of the gene therapy systems can be used as very efficient vectors. Data from animal experiments from different laboratories are promising. Still much effort has to be put into research on the exact – cytokine driven – migration in order to rely on such mechanisms for human brain tumor treatment.

d. Innovative aspects

The department of Neurosurgery has expertise in the set-up of experimental research for cell therapy in neurodegenerative diseases as well as in the set-up for conducting clinical trials to evaluate stem cell based cell therapy. The department has a history of decades for treatment of Parkinson’s disease, both medical and neurosurgical, in collaboration between the departments of Neurology and Neurosurgery. The use of chemokine driven migration of neural stem cells for the local delivery of therapeutic agents is a novel approach to treat glial tumors.

e. References

1. HogenEsch RI, Staal MJ, et al. Utility of fragmented human fetal tissue, as a potential dopaminergic brain graft in Parkinson’s disease. Stereotact Funct Neurosurg 1993;61:1-11

2. Roon WMC van, Copray JCVM, HogenEsch RI, Staal MJ, Go KG. Fetal porcine mesencephalon grafts: dissection procedure and cellular characterization in culture.

Res Neurol Neurosci 1995;7:199-205

3. Molenaar GJ, HogenEsch RI, Staal MJ, Sprengers MES. Ontogenesis of embryonic

porcine ventral mesencephalon in the perspective of its potential use as a xenograft in Parkinson’s Disease. J Comp Neurol 1997; 382:19-82.

4. HogenEsch RI, Koopmans J, Copray JCVM, van Roon WMC, Kema I, Molenaar G, Go KG, Staal MJ. Fetal porcine ventral mesencephalon graft. Determination of the optimal gestational age for implantation in Parkinsonian patients. Exp Brain Res 2000;132:345-350

5. Koopmans J, HogenEsch I, Copray S, Middel B, van Dijk H, Go KG, Staal M.Cryopreservation of porcine fetal ventral mesencephalic tissue for intrastriatal transplantation in Parkinson's disease. Cell Transplant 10(7):573-81, 2001