Our goal is to develop a cellular strategy for repairing the damage seen in children's myelin disease, Multiple Sclerosis and other neurological diseases.

 
Dr. Seung U. Kim updates progress with his stem cell research -

As I informed you earlier, we are conducting several interesting projects here at UBC and also in Suwon, Korea:


1. New human neural stem cell lines - Since our immortalized human neural stem cell (hNSC, F3) line was generated using v-myc oncogene, institutional review boards including one at UBC are reluctant to grant permission to use the cell line for the clinical trials in neurological diseases. To circumvent this issue, we have recently generated a new hNSC cell line using tet-on-vmyc system (G12). In this system, v-myc is only activated in the presence of tetracycline antibiotic, thus in the absence of tetracycline, the immortalized hNSCs do not multiply. We will develop this G12 hNSC cell line further and utilize it for animal studies and clinical trials.

2. Huntington disease (HD) - We have proactively grafted F3 hNSC cells in rat model of HD and grafted F3 cells protected host neurons from cell death (a paper submitted for publication). Dr. B. Levitte of UBC has generated a transgenic HD mouse model, and he kindly offered his animals for hNSC transplantation. The first experiment will take place next week.

3. Parkinson disease (PD) - We have generated subline of F3 hNSC carrying TH and GTPCH genes so that this subline produces L-DOPA 2000 times over the parental cells.

L-DOPA is the precursor of dopamine which is deficient in PD brain. We initiated animal studies in rat PD models at UBC in the collaboration with Dr. C. Lee who is a specialist of PD here.

4. ALS - When F3 hNSCs were injected into the tail vein of mouse ALS model (carrying mutant superoxide dismutase/ SOD gene), F3-turned-neurons were found in hippocampus 2-3 weeks later. We are currently doing long-term follow up to see if F3 cells arrive at spinal cord lesions. This project is carried out in Suwon, Korea. If this work produces positive results, we expect to initiate a clinical trials in Korea.

5. Stroke - My collaborators at the Seoul University Hospital (my alma mater) has published two papers (one in focal ischemia model and the other in cerebral hemorrhage model). F3 hNSCs were injected into tail vein of rat stroke models and later they migrated into the perilesion sites and then induced improvement in functional parameters such as corner test or rotarod tests. We have recently generated F3.BDNF and F3.GDNF sublines carrying neurotrophic factor genes. These modified hNSCs should provide protection of neurons from cell death. We will provide these cell lines to the investigators to graft into the stroke model animals.

6. Pediatirc storage diseases - Prof. Eto of Tokyo has completed a work in which F3 hNSCs carrying beta-glucuronidase gene coreect clinical course and pathology of Sly disease (mucopolysaccharidosis VII) animals. His group is currently working in the area of Krabbe and Gauchet diseases using F3 hNSCs. I am interested in collaborating again with Kyushu University investigators who carry adrenoleukodystrophy (ALD) transgenic mice (Yamada who came to Canada several years ago is no longer with the group) and we will generate G12 hNSCs overexpressing ALDP gene and transplant into ALD mice (we obtained ALDP cDNA recently).

7. Brain tumor/ glioma � Dr. Karen Aboody (former fellow of Evan Snyder and currently at the City of Hope Medical Center) has generated most exciting findings for F3 hNSCs to be used for treatment of brain tumor. F3 hNSCs could selectively and specifically migrate into brain tumor loci when grafted into the tumor carrying animals. In collaboration with her, we are currently producing F3 hNSCs carrying suicidal genes such as cytosine deaminase (CD) or HSV-TK (herpes virus thymidine kinase). F3.CD or F3.TK cells when they are grafted into the brain or intravenously injected, should migrate into the brain tumor loci and when drugs such as fluorocytosine or gancyclovile are applied, hNSCs commit suicide and release anticancer drug and kill the tumor cells by ?�by-stander-effect?�. Since F3 cells kill themselves later, the question of V-myc oncogene is non-issue here. I am certain clinical trials in brain tumor/gliobastoma could be the first one for the hNSCs we generated. We are determined to generate F3.CD and F3.HSVTK cell lines within a month or two.

8. We have generated immortalized cell lines of human bone marrow stem cells (from fetal bone marrow) using retroviral vectors carrying v-myc (as in hNSC F3 line) or teromerase gene. The hBMSC cell line generated is quite unique since it carrys teromerase which is physiological and does not cause tumor formation. HBMSC cell lines we produced are pluripotent and they could transdifferentiate into bone, cartilage, fat cells and neurons (these results are most recent). It appears that hBMSCs has endless potential for clinical application much more than ES cells everybody are talking about.

posted by Canadian Myelin Research Initiative at 3:31 PM