公募シンポジウム３：脊髄損傷の機能回復に迫る分子と治療薬
Symposium3 : Molecules and therapeutic strategies for functional recovery of spinal cord injury |
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| 2020/9/10 10:50～11:20 Zoom B
SY3-01
脊髄損傷慢性期の機能回復に有効な薬物と分子
Therapeutic drugs and molecules for functional recovery in chronic spinal cord injury
*東田 千尋1
1. 富山大学 和漢医薬学総合研究所
*Chihiro Tohda1
1. Institute of Natural Medicine, University of Toyama
Chronic spinal cord injury (SCI) is difficult to cure. Although the majority of SCI studies have focused on the nervous system and inflammatory cells in the spinal cord, we targeted skeletal muscle atrophy, as a characteristic finding in the chronic phase. Because, a longitudinal study showed that skeletal muscle atrophy progresses in a manner dependent on the time after injury in humans. Disuse of skeletal muscle and loss of motor neurons synergistically induce muscle atrophy. On the contrary, exercise was shown to slightly improve motor function when applied during the chronic phase. Although skeletal muscle secretes myokines responded to muscle activity, we considered that some myokines might regulate neural function. Thus, we hypothesized that stimulation of skeletal muscle with drugs rather than exercise might activate the release of known or yet unknown myokines, with the notion that the identification of such drugs and new myokines would pave a new way of therapy for SCI.
We explored drugs that protect against muscle atrophy and activate secretion of axonal growth factors from skeletal muscle, and found that acteoside induced the secretion of axonal growth factors from skeletal muscle cells and proliferation of these cells. Intramuscular injection of acteoside in mice with chronic SCI recovered skeletal muscle weight reduction and motor function impairment. We also identified pyruvate kinase isoform M2 (PKM2) as a secreted factor from skeletal muscle cells, stimulated by acteoside. Extracellular PKM2 enhanced proliferation of skeletal muscle cells and axonal growth in cultured neurons. Sustained i.c.v. infusion (i.c.v.) of PKM2 significantly recovered motor function and axonal growth in chronic SCI mice. These results indicate that effects of acteoside on chronic SCI might be mediated by muscle-derived PKM2-evoked axonal growth. This study proposes that the candidate drug acteoside and a new myokine, PKM2, could be used for the treatment of chronic SCI.
| | 2020/9/10 11:20～11:50 Zoom B
SY3-02
内在性Nogo受容体アンタゴニストLOTUSの 脊髄損傷治療法への適用
Application of an endogenous Nogo receptor antagonist LOTUS to therapy for spinal cord injury
*竹居 光太郎1
1. 横浜市立大学大学院生命医科学研究科
*Kohtaro Takei1
1. Yokohama City University Graduate School of Medical Life Science
Brain injury, such as spinal cord injury (SCI), results in severe sensory and motor deficits due to the poor regenerative capacity of the adult central nervous system (CNS) primarily caused by a damaged CNS environment containing a large amount of axonal growth inhibitors, such as Nogo receptor-1 (NgR1), which inhibits axonal regrowth strongly after SCI, and its five ligands. Lateral olfactory tract usher substance (LOTUS), identified in the developing brain, completely antagonizes NgR1 function, promoting neuronal regeneration and functional recovery after SCI. LOTUS consists of the membrane-bound form and the secreted soluble form. We found that both type of LOTUS interacts with NgR1 and blocks NgR1-mediated signaling. Furthermore, we recently found that LOTUS also exerts suppression on another axonal growth-inhibiting receptor paired immunogloblin-like receptor (PIR)-B. Therefore, we hypothesized that LOTUS mightbe a useful natural agent for the clinical treatment of SCI in order to increase functional recovery by converting the CNS environment from nonpermissive to permissive for neuronal regeneration. We examined the role of LOTUS in promoting functional recovery and neural repair after SCI. Wild-type untreated mice show incomplete but substantial intrinsic motor recovery after SCI, whereas the genetic deletion of LOTUS delays and decreases the extent of motor recovery. The neuronal overexpression of LOTUS in transgenic mice promotes motor recovery after SCI. Furthermore, the administration of purified recombinant LOTUS protein in injured site also promotes motor recovery after SCI. In addition, recombinant viral overexpression or administration of purified LOTUS protein enhances retinal ganglion cell axonal regeneration after optic nerve crush. These findings suggest that LOTUS can be used for therapeutic natural agent in nerve repair and may have potential for the clinical treatment of humans with SCI. I will discuss future perspective of therapeutic strategy using LOTUS.
| | 2020/9/10 11:50～12:20 Zoom B
SY3-03
脊髄損傷急性期における顆粒球コロニー刺激因子の神経保護作用：基礎から臨床まで
Granulocyte colony-stimulating factor-mediated neuroprotective therapy for acute spinal cord injury: from bench to bedside
*國府田 正雄1、大鳥 精司2、花岡 英紀2、山崎 正志1
1. 筑波大学、2. 千葉大学
*Masao Koda1, Seiji Ohtori2, Hideki Hanaoka2, Masashi Yamazaki1
1. University of Tsukuba, 2. Chiba University
Introduction
Granulocyte Colony Stimulating Factor (G-CSF) is generally used for neutropenia. Previously, we showed through the animal experiments that G-CSF promoted neurological recovery after spinal cord injury (SCI) via various mechanisms. Next we moved to early phase of clinical trials. In a phase 1/2a trial, no adverse events were observed. Next, we conducted a non-randomized, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. We are now performing a phase 3 trial to confirm G-CSF treatment efficacy for acute SCI.
Materials and Methods
The current trial included cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C) within 48 hours after injury. Patients were re-assessed for neurological status at 48 hours after injury, and those whose palsy is AIS B or C were enrolled. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/d×5d of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety was evaluated by blinded observer. A total of 88 patients (44 cases in both groups) were enrolled to this trial.
Our primary endpoint was changes in ASIA motor scores from baseline to 3 months after drug administration. Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association.
Results
The acquired ASIA motor score from baseline to 6 and 12 months after drug administration in patients with age over 65 tended to be larger in the G-CSF group than that in the placebo group. However, there was no significant difference in primary endpoint between both groups in all the patients.
Conclusion
G-CSF might be effective for acute SCI in aged patients.
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