Treatment for neurological diseases has been limited by the presence of the protective blood-brain barrier. Recent studies from our laboratory have shown that direct intraventricular implantation of microcapsules containing genetically modified cells can effectively deliver the transgene product to the mouse brain, thereby circumventing the blood-brain barrier. In this thesis, the experiments were aimed at scaling up the murine experiments to determine if direct implantation of alginate-poly-L-lysine-alginate microcapsules to the central nervous system of dogs was a feasible means of treating the large animal brain. In the first two experiments reported here, microcapsules containing cells genetically modified to secrete human growth hormone were injected into the central nervous system of dogs. Two routes of delivery were examined, intraventricular brain surgery and injection into the spinal intrathecal space (cisterna magna). While empty capsules within the central nervous system were benign, microcapsules containing cells induced an acute inflammatory response in the brain and spinal cord tissue, irrespective of the route of delivery. Human growth hormone was detected transiently in four of six dogs, but the data were interpreted with caution due to extraneous variables such as compromised microcapsules in two of the dogs and previous systemic treatment in six of the other dogs. In the last experiment, microcapsules containing cells genetically modified to secrete the lysosomal enzyme a-L-iduronidase were implanted into the lateral ventricles of a dog with Mucopolysaccharidosis type I in an attempt to correct the characteristic neuronal pathology. An immune response ensued and appeared to abolish any possible effect of the microcapsule treatment. The experiments presented here demonstrate the challenges and obstacles that need to be overcome to effectively scale up therapies from rodent experiments to large animals. The data also shed light on the immunological complications that may arise with invasive and repeated treatment in the central nervous system of large animals. / Thesis / Master of Science (MS)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24273 |
| Date | 09 1900 |
| Creators | Barsoum, Susan |
| Contributors | Chang, P. L., Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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