中枢神経疾患治療に対するトランスレーショナルリサーチの現状とその課題 Current state and issue of translational research for CNS repair
S2-5-2-1 脳梗塞患者に対する自己骨髄単核球細胞を用いた血管再生治療の臨床試験 Autologous bone marrow mononuclear cells transplantation for stroke patients ○田口明彦1 ○Akihiko Taguchi1 先端医療振興財団先端医療センター再生医療研究部1 Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovasion1 We had demonstrated that intravenous administration of bone marrow derived mononuclear cells improves functional recovery through enhanced angiogenesis in experimental stroke model. Cell based-therapies using autologous bone marrow derived mononuclear cells were initiated in patients with limb and myocardial ischemia with promising results. Based on these observations, we have started phase 1/2a clinical trial of cell-based therapy for patients with cardiogenic cerebral embolism (ClinicalTrials.gov ID: NCT01028794). Major inclusion criteria is the patient diagnosed with sever cardiogenic cerebral embolism (more than 9 in NIHSS score at day 7 after onset of stroke) in age 75 or younger. Patient has 25ml (low dose group, n=6) or 50ml (high dose group, n=6) of bone marrow aspiration on day 7-10 after onset of stroke. Autologous bone marrow derived mononuclear cells are purified by density gradient method and administrated intravenously in the day of cell aspiration. Primary endpoint is the safety and improvement of NIHSS, compared with our historical control. As the results, we have treated 12 patients and no adverse effects were observed so far. Most of the patients showed significant improvement of neurological function at 6 months after cell transplantation. No enrolled patients showed worsening of NIHSS score at 30 days after treatment, compared with before treatment. As the conclusion, autologous bone marrow mononuclear cells transplantation is likely to be safe, feasible and improve functional recovery. We are in preparation of confirmatory clinical trial as the next step.	S2-5-2-2 脊髄損傷慢性期における自家嗅粘膜移植術 Olfactory mucosa autografts for chronic spinal cord injury ○吉峰俊樹1, 岩月幸一1, 大西諭一郎1, 森脇崇1, 石原正浩1, 梅垣昌士1,3, 田島文博2, 山海嘉之3 ○Toshiki Yoshimine1, Koichi Iwatsuki1, Yuichirou Ohnishi1, Takasi Moriwaki1, Masahiro Ishihara1, Masashi Umegaki1,3, Fumihoro Tajima2, Yoshiyuki Sankai3 大阪大学大学院医学系研究科脳神経外科学1, 和歌県立医科大学　リハビリテーション科2, 筑波大学大学院システム情報工学科3 Dept Neurosurg, Osaka Univ Med School, Osaka, Japan1, Department of Rehabilitation Medicine, Wakayama Medical University, Wakayama, Japan2, Center for Cybernics Research, University of Tsukuba3 The olfactory mucosa (OM) is a part of the nasal mucosa which contains neural stem-like progenitor cells and olfactory ensheathing cells (OECs). Our previous studies with rat spinal cord transection demonstrated partial functional recovery after transplantation of OM. Since OM is readily accessible by nasal endoscopy, we conducted a clinical pilot study using olfactory mucosa autografts (OMA) in patients with complete paraplegia after spinal cord injury. Four patients with complete paraplegia (AIS grade A) after spinal cord injury were enrolled in the study; the age 19-40 years old, 2 males, the size of the lesion 1.7-2.8 cm, located at Th4/4-11/12. The duration after injury was 1 year and 5months to 24 year and 9 months. All of them were rehabilitated at least 1 year. Six to 12 months after implantation, voluntary muscle movements and EMG were observed in two patients (AIS grade C). Sensory function was not improved in any patient. No major adverse effects were recognized after surgery. Our pilot study demonstrated OMA is safe and partially effective in patients with severe spinal cord injury. The results are, however, not enough satisfactory because (1) it was not effective in all patients, (2) the degree of recovery was limited, and (3) intensive rehabilitation was required for few years after implantation. We would discuss what might be required to further improve the outcome. It may not be enough to repair the spinal cord in patients with chronic stage of complete paraplegia. The major difficulties in the regenerative therapy of the central nervous system are also discussed.
S2-5-2-3 パーキンソン病の遺伝子治療ー現状と課題 Gene therapy for Parkinson's disease: Advances and challenges ○村松慎一1 ○Shin-ichi Muramatsu1 自治医科大学神経内科学1 Division of Neurology, Jichi Medical University1 Parkinson's disease (PD) is a common neurodegenerative disorder among the elderly. The cause of PD largely remains unknown and there is currently no curative therapy. Although virtually all PD patients benefit clinically from L-dopa therapy, as the disease progresses, L-dopa is not efficiently converted to dopamine in the striatum and becomes less effective. Thus, novel therapeutic interventions, including gene therapy, are required. The main pathological lesions of PD are in the well-defined nigrostriatal dopaminergic system and therapeutic genes are primarily delivered to a portion of the basal ganglia where stereotactic surgical techniques are well established in clinical practice. Viral vectors, in particular vectors derived from adeno-associated virus (AAV), are suitable for the transduction of neurons in the mammalian brain without significant toxicity. Current clinical trials of gene therapy for PD are based on 3 strategies. 1. To restore the local production of dopamine by introducing genes associated with dopamine-synthesizing enzymes into the putamen. 2. To protect nigro-striatal projection by delivering the neurturin or glial cell line-derived neurotrophic factor (GDNF) gene, both to the putamen and the substantia nigra. 3. To modulate neural activity by transducing the subthalamic nucleus with vectors expressing glutamic acid decarboxylase (GAD). Initial results of phase I studies, including our own, indicate that all of these strategies are promising. More recently, results of a phase II double-blind study of the GAD strategy showed significant beneficial effects of GAD delivery over the sham operation group. Despite these positive outcomes, gene therapy has not yet gained a strong foot-fold on the market and the company that sponsored the GAD study has become insolvent. It may be necessary to develop more efficient production of vectors and to establish a profitable business model. Rapid regulatory approval is also desirable.	S2-5-2-4 認知症患者に対する新規メカニズムに基づく薬物治療 Novel mechanism and therapy to treat patients with dementia ○猪原匡史1 ○Masafumi Ihara1 先端医療振興財団先端医療センター再生医療研究部1 Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovasion1 With the demographic shift in age in advanced countries inexorably set to progress in the 21st century, dementia will become one of the most important health problems worldwide. The discouraging results of the immunotherapy clinical trials for Alzheimer's disease have shifted scientific attention from the mechanism underlying ß amyloid (Aß) synthesis toward clearance, including a perivascular drainage pathway for interstitial fluid containing Aß. Theoretical models indicate that arterial pulsations may be the motive force for the drainage of interstitial fluid and solutes. As arteries stiffen with age or with other co-morbid factors, the amplitude of pulsations is reduced, perivascular drainage of Aß becomes less efficient, and insoluble Aß is deposited in the drainage pathways as cerebral amyloid angiopathy. This notion is supported by the finding that the distribution of Aß deposits in the basement membranes of cerebral capillaries and arteries corresponds very closely with the perivascular drainage route. Therefore, therapeutic strategies that enhance the patency of this perivascular drainage pathway with vasoactive drugs may facilitate Aß removal and help prevent cognitive decline in the elderly. Based on this emerging paradigm, we are planning a clinical trial to test whether such a strategy is effective to halt cognitive decline as a preemptive medicine in patients with mild cognitive impairment.

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