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Youmans:脊髓受損疾病與治療-4(完)

WCH | 2021-06-24 11:24:06 | 巴幣 104 | 人氣 216


細胞移植治療

  • Because limited substrate for neural repair is a significant obstacle following SCI, cell-replacement strategies are believed to be among the most promising new strategies for treating SCI. Various cell types have been tried with varying goals. Some researchers aim to produce new neurons that will integrate into functional circuits, whereas others have sought and achieved oligodendrocyte differentiation and remyelination. Despite diverse strategies, functional benefit has been consistently seen, although as yet the magnitude of this benefit has been uniformly modest.
因為對於神經修復的技術有限對於脊髓受損的治療是很大的障礙,因此最新的治療策略開始考慮細胞移植。有很多種不同的細胞可以用來移植。有些研究者矢志於生產新的神經元來恢復功能,而有些則透過活化寡樹突細胞的分化與髓鞘再生。但無論如何這些一直都被認為對神經功能有利的,即便這種好處通常都被低估。

一、活化自體巨噬細胞

  • The ProCord trials are noteworthy for being the first human trials of cellular transplantation for SCI. The basis for this approach comes from work by Michal Schwartz in the 1990s demonstrating that autologous macrophages activated ex vivo by peripheral myelin could promote functional recovery when injected into an animal model of SCI. Possible mechanisms of action include augmented clearance of myelin debris, enhanced synthesis of beneficial trophic factors interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF), and decreased synthesis of the harmful factor TNF-α.
ProCord試驗身為第一個人類脊髓受損細胞移植試驗是很值得一看的。最早是在1990年代,透過活化抽離自周邊髓磷脂的自體巨噬細胞,注射進動物來刺激神經功能回復。可能的原因包含清除髓磷脂殘渣、促進有利的營養因子IL-1β和BDNF或是減少有害因子TNF-α。
  • On the basis of these results, the technology was commercialized by Proneuron Biotechnologics, Inc. (New York), and two clinical trials for human SCI were launched. The first enrolled eight patients with complete SCI, and the subjects underwent transplantation within 14 days of injury. The results of this initial study, published in 2005, reported that three of the patients, who had ASIA Impairment Scale grade A SCI, recovered to ASIA grade C status, and no major adverse events related to the cell transplants were encountered. This encouraging result led to the subsequent multicenter phase 2 ProCord trial in Israel and the United States, which included a control group. The trial was suspended prematurely in the spring of 2006 for financial reasons. Fortunately the results of this incomplete trial have now been published. They suggested harm related to autologous macrophage transplantation that was nearly statistically significant in comparison with data from a nontransplanted control group ( P = .053 for ASIA grade improvement). The numbers of adverse events were, however, no different between the two groups ( P = .942).
因為得到這個結果,第二階段人體試驗也接續展開。一開始有8名病患參與,在脊髓受損的14天內接受移植。最後結果發表於2005年,聲稱有3名病患原本ASIA等級A的進步到等級C,同時也沒有很主要的副作用。這結果也促進了後續多中心第二階段試驗的進行,源自以色列和美國,並額外加入了控制組。但這個試驗在2006年春天就被腰斬,因為經費不足。好在的是他們仍將未完成的結果發表出來,聲稱實驗組和控制組之間沒有太大的副作用差異。

二、許旺細胞

  • Schwann cells, the myelinating cells of the PNS, are believed to be permissive of regeneration similar to that of the peripheral nerve grafts employed by Richardson and colleagues. Another potential benefit of these cells is their ability to be harvested from an autologous source, such as the sural nerve, negating the need for immunosuppression following transplantation. The work of Dr. Bunge and colleagues at the Miami Project has explored putative benefits of Schwann cell transplantation for SCI since the early 1990s. A limitation of this technique appears to be that even though regenerating CNS axons readily grow into the permissive environment that these cells provide, the axons are not prone to growing out of the cells and back into the hostile CNS environment. Nonetheless, a phase 1 clinical trial assessing the safety of autologous Schwann cell transplantation for human SCI has been initiated at the Miami Project (NCT01739023). This study will enroll patients strictly within 7 days of a complete SCI.
許旺細胞是周邊神經有髓鞘的細胞。被認為跟過去研究就發現移植的周邊神經一樣可以促進神經再生。另一個好處就是許旺細胞可以從自體身上蒐集得到,例如從腓腸神經。從自體移植就比較能減少免疫抑制劑的需要。最早的研究開始於1990年代。當時的技術有限,導致中樞神經雖然可以在比較好生長的環境中長出軸突,但回去原本宿主身上就長不出來。而現在也開始了第一期臨床試驗,研究如何安全地把許旺細胞做自體移植。這個試驗找了七天內有完全脊髓損傷的病患參與

三、嗅鞘細胞

  • Olfactory ensheathing cells (OECs) are specialized glia of the olfactory system that escort regenerating axons of olfactory receptor neurons from the PNS of the nasal epithelium to the “hostile” CNS of the olfactory bulb. This property has made them of interest to scientists given that may address the “PNS to CNS” barrier inherent in Schwann cells. Promising preclinical data exploring their transplantation for SCI have been mixed with concern that the observed benefit may actually result from remyelination by Schwann cells that contaminate OEC cultures and also bear the p75 marker.
嗅鞘細胞是嗅覺系統中特化的膠細胞,是可以將鼻腔表皮的周邊神經所生產的再生嗅覺受器軸突,運送到扮演宿主角色的中樞神經嗅球。這個功能使得科學家想到或許可以藉此將許旺細胞從周邊神經運到中樞神經。而臨床前的資料也開始用來討論許旺細胞混合了嗅鞘細胞和p75標記能不能用在脊髓受損的移植上。
  • A high-quality human study of OECs was completed by physicians affiliated with Griffith University in Brisbane, Australia. They conducted a single-blind trial in which “purified” autologous OECs were transplanted into three patients with complete thoracic SCI within 6 to 32 months of injury. Comparison was made with matched but nontransplanted controls. Three-year follow-up data showed no motor improvement but also an absence of surgical complications.
一個很高品質的人體研究在澳洲完成,採用了單盲試驗並將純化的嗅鞘細胞移植到3個6-32個月前完全胸椎損傷的病患身上。這研究沒有跟對照組比較,而三年追蹤下來發現沒有運動功能改善但也沒有手術的併發症。
  • A Polish group reported a phase 1 study assessing the safety and feasibility of transplanting OECs and fibroblasts into three patients with complete SCI more than 6 months after injury. Comparison was made with three nontransplanted controls; rehabilitation was co-administered. The investigators reported neurological improvement in all of the patients with one moving to ASIA Impairment Scale grade B and another to grade C by 12 months after the procedure. Notably, improvements were noted on diffusion tensor imaging MRI as well as neurophysiologic parameters. No adverse effects, such as neuropathic pain, were seen. The investigators correctly stated that few conclusions should be drawn from this small study.
另一個波蘭研究小組則發表了第一期研究,關於嗅鞘細胞移植的安全性與可行性。他們找了3個玩元脊髓損傷超過6個月的病患。這個研究有跟對照組做比較,而研究的病患都有在住院的時候另外做復健。最後發現一個病患進步到ASIA等級B,而另一個則進步到等級C。值得注意的是在核磁共振上也看到有所改善。移植沒有副作用例如神經痛。研究員最後覺得這個小研究是有一些結論可以參考的。
  • OEC transplantation for human SCI was also performed in an uncontrolled Portuguese pilot study. Seven patients with ASIA grade A SCI were treated with autologous olfactory mucosal implants at 6 months to 6.5 years after injury. Apparently, all patients had improvement in ASIA motor scores, with two progressing from ASIA grade A to grade C. Additionally, two patients reported return of sensation in their bladders, and one regained voluntary anal sphincter contraction.
嗅鞘細胞移植另外也在葡萄牙中進行了無對照組的研究。有7位ASIA等級A的病患在受傷後6個月至6.5年後接受自體嗅鞘細胞移植。很明顯的這些病患ASIA等級中運動分數都有改善,其中有兩個還進步到等級C。此外有兩位病患發現膀胱感覺有恢復,而一個則恢復了括約肌收縮功能。
  • China has the world's largest experience with a cell transplantation approach for SCI. A group led by Huang transplanted olfactory tissue from aborted fetuses into the spinal cords of more than 300 patients, but unfortunately the selection of patients, the acquisition and characterization of the transplanted tissue, and the outcome evaluation lacked scientific methodology. Later a group in Luongyang reported transplanting OECs into chronically injured human spinal cords twice weekly for 4 weeks in an uncontrolled study of eight patients. “Substantial” sensorimotor improvement was reported in three patients. Another group in Beijing reported modest neurological improvement in 11 patients transplanted according to Huang's protocol.
中國則展開了全世界最大的黃氏細胞移植研究,從墮胎胎兒身上獲取嗅覺組織來移植進超過300名病患。但很不幸地從病患的選擇、獲取移植組織的方法和其成分、以及對於結果的評估都缺乏科學的方法。最近中國洛陽發表了移植嗅鞘細胞進去慢性脊髓損傷病患每周兩次為期四周的無對照組研究,有8名病患參與。其中有3名病患有「重大的」感覺運動功能改善。另外在中國北京也發表黃氏細胞移植研究中有11位病患有些許的神經功能改善。

四、骨髓基質細胞

  • Bone marrow stromal cells (BMSCs) migrate to the site of CNS injury following intravascular or intrathecal administration, albeit at a low rate. Importantly, they can also be transplanted in autologous fashion like Schwann cells and OECs. Many authorities believe that these cells may elaborate beneficial trophins into tissue, although numerous other mechanisms of action are possible. A number of groups are currently transplanting BMSCs into the injured spinal cords of human patients and are reporting benefit. These claims of neurological efficacy need to be interpreted very cautiously because the trials are small and generally have been conducted without controls or blinded observers.
骨髓基質細胞少部分會在中樞神經受損後移過去到血管內或髓鞘內。重要的是它跟許旺細胞或是嗅鞘細胞一樣都能自體移植。很多專家認為骨髓基質細胞可以對組織提供養分,雖然還是有可能有其他機轉還沒被發現。最近有一定數量的研究小組開始將骨髓基質細胞移植進受傷的脊髓並發現是有好處的。但這個好處還是要謹慎評估因為這些試驗規模都很少並且沒有控制組或是盲測。
  • A Korean group has reported the results of autologous human BMSC transplantation combined with administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in a phase 1/2 open-label, nonrandomized study. This trial involved 35 patients with ASIA grade A status who underwent transplantation within 14 days (n = 17; acute), between 14 days and 8 weeks (n = 6; subacute), or more than 8 weeks (n = 12; chronic) after injury; 13 control patients were treated with decompression and fusion only. This treatment led to improved neurological function in 30.4% of patients in the acute and subacute groups, but no significant improvement was observed in the chronic group.
一個韓國的研究小組發表了自體骨髓基質細胞移植外加GM-CSF應用的第一第二期開放式無對照組的研究。這個研究找了35名ASIA等級A的病患在受傷的14天內(急性)、14天至8周(亞急性)或是8周以後(慢性)進行移植。其中有13名控制組的病患只有進行減壓和骨融合手術。最後發現在急性和亞急性病患中有30.4%神經功能有改善,但在慢性組沒有顯著的改善。
  • Investigators in Prague have also studied BMSCs in humans. Their trial involved 20 patients with complete SCI who underwent transplantation 10 to 467 days after injury. Improvement in motor and/or sensory functions was noted in 5 of the 7 patients with acute (10-30 days after injury) SCI and in 1 of 13 patients with chronic (2-17 months after injury) SCI, leading the researchers to suggest a therapeutic window of 3 to 4 weeks following injury.
布拉格也開始進行骨髓基質細胞的人體研究,找了20名完全脊髓受損的病患在受傷後10-467天後進行移植。其中7名急性(受傷後10-30天)病患中有5名運動感覺功能有改善,而在13名慢性(受傷後2-17個月)病患中只有1名有改善。這個研究因此結論出在受傷後3-4周內是移植的黃金期。
  • An Egyptian group co-administered BMSCs along with sural nerve grafts and a chitosan-laminin paste in 14 patients with chronic SCI. This interesting combinatorial approach yielded an improvement in ASIA Impairment Scale grade in all patients, with 12 experiencing improvement to grade C, although the trial was uncontrolled and no patient regained the ability to stand.
一個埃及的研究將骨髓基質細胞和chitosan-laminin物質做結合移植到14名慢性脊髓損傷的病患。這研究發現所有病患的ASIA等級都有改善,其中有12名進步到等級C。雖然這個試驗無對照組同時也沒有病患因此能恢復站立功能。
  • A study from Iran reported on co-administration of bone marrow stromal cells with Schwann cells to patients with chronic SCI. Negligible benefit was noted at a mean follow-up of 24 months after transplantation. Also observed was an absence of anomalies on MRI. A nonrandomized but controlled trial of BMSC transplantation into subacutely injured human patients via lumbar puncture and intrathecal infusion was performed also in Iran. A trend toward significant improvement was seen in treated patients in comparison with controls. No adverse events were seen in either the study or the control group in this trial.
伊朗的研究則將骨髓基質細胞和許旺細胞移植進慢性脊髓損傷的病患。移植後24個月的追蹤發現好處是微不足道的,但同時也發現核磁共振沒有異常的表現。另一個非隨機但有控制組的研究也在伊朗進行,透過脊髓穿刺的方式將骨髓基質細胞移植進亞急性脊髓損傷的病患。結果顯示有移植的相比之下有顯著的改善,同時兩者也沒看到副作用。
  • A group in Beijing reported transplantation of human umbilical cord mesenchymal cells into the injured spinal cords of 22 patients in an uncontrolled trial. It is uncertain whether their injuries were acute or chronic. Patients received one to three courses of transplantation and the duration of follow-up was 3 months to 3 years. Benefit was reported in 13 of the 22 patients; 81% of patients with incomplete injuries showed benefit. No treatment-related adverse events were seen.
中國北京發表了用臍帶間質幹細胞移植到22名病患的無對照組試驗,但對於病患是急性還是亞急性無從得知。病患進行三期臨床試驗後追蹤了3個月至3年,在這些病患中有13名有發現好處,81%的未完全受損病患有發現好處,同時也沒發現有治療相關的副作用。
  • A similar study involving BMSC infusion via lumbar puncture was conducted in Japan and published in 2012. The subjects were patients with ASIA grade A acute tetraplegia. Cells were harvested during spinal fusion surgery. Patients were monitored for up to 4 years after transplantation. No adverse events were seen, and “remarkable” improvement was observed in those with initially incomplete injuries.
另一個類似的研究也在日本於2012年發表,找了ASIA等級A且全攤的病患。骨髓基質細胞是從脊髓融合手術中獲取,病患也在移植後追蹤4個月。沒有發現副作用,也發現對於一開始是不完全損傷的病患有「很顯著」的改善。

五、神經幹細胞

  • Researchers at the University of California, Irvine, have reported extensively on the transplantation of oligodendrocyte progenitor cells derived from human embryonic stem cells in a rodent model of SCI. Transplantation of these cells achieves remyelination of spared, demyelinated spinal cord axons, and the observation of tissue sparing has suggested an additional neuroprotective effect. To facilitate translation, the laboratory developed a technique to ensure high purity of the cell isolates as well as techniques for culturing the cells without feeder cells, use of which could otherwise lead to viral contamination or nonhuman polysaccharide epitopes on the surfaces of transplanted cells. This work allowed Geron Corporation (Menlo Park, CA) to initiate a phase 1 human clinical trial with this cell type. For ethical reasons the trial enrolled patients with ASIA Impairment Scale grade A SCI. Unfortunately these patients have limited capacity for recovery, so the chances that this trial would show a benefit were very low. A substantial additional financial investment would be required before such an effect could be seen. Geron thus enrolled only a small number of patients in this landmark trial prior to its cessation. The technology and intellectual property were purchased by Asterias Biotherapeutics, Inc. (Fremont, CA), which completed the planned enrollment of five patients in the phase 1 trial in July of 2013. We anxiously await the results of 1-year follow-up data from this trial and word on a phase 2 trial.
加州大學的研究員廣泛地發表了從人類胚胎幹細胞形成的寡樹突前驅細胞,用來移植進脊髓受損的研究。這些細胞成功的使得原本保留的去髓鞘脊髓軸突髓鞘再生。而發現到組織能夠被保留也說明了這一職有神經保護的功能。為了使得移植可行,研究採用了高度純化細胞的技術,並不用傳統的培養皿來培育細胞,因為培養皿可能會導致病毒感染或是一些非人體的多醣體抗原表面附著於細胞身上。這個研究用在第一期的人體試驗,找來了ASIA等級A的病患參與。不幸的是這些病患本來就有治癒上的限制,所以這個治療最後可能效益很低。就算要看到成效也需要大量資金的投入。因此這個試驗只找了很少人來進行。第一期試驗在2013年7月找了5位病患參與,本書很渴望知道一年後的追蹤以及能否進入第二期試驗。
  • Several additional human trials of human stem and neural progenitor cells are ongoing or planned. A trial being conducted by StemCells, Inc. (Newark, CA), is performing transplantation in patients with subacute thoracic SCI a minimum of 6 weeks after injury (NCT01321333). This phase 1/2 trial was initiated in 2011 and seeks to enroll 12 patients. A second trial by StemCells, Inc., began to enroll 52 patients with cervical SCI in a phase 2 trial beginning in August 2014 (NCT02163876). The study is single-blind and randomly allocates patients to treatment or no treatment a minimum of 12 weeks after their injuries. Another phase 1/2 trial involving the transplantation of human neural stem cells 3 to 12 months after SCI is being conducted by the University of Zurich, and we await its details.
一些額外的人體幹細胞和神經前驅細胞的人體試驗也在進行。一個加州的公司找了亞急性胸椎受損至少6周後的病患做實驗。第一第二期臨床試驗在2011年啟動並找了12位病患參與。而在2014年8月這公司對頸椎受損病患進行第二期試驗。這個研究找了52名病患參與,採取單盲以及隨機將病患在受傷後至少12周隨機分到治療或未治療組。另一個由蘇黎世大學發表的第一第二期試驗研究病患在受傷後3-12個月後給予神經幹細胞的治療,這裡本書正等待著結果。

結論

  • The SCI field is advancing rapidly and novel insights are being paired with lessons learned from a generation of unsuccessful human clinical trials. Several promising therapeutics are being investigated in new studies, and the possibility that at least one of these treatments will be of benefit in SCI is high. Although an outright cure is unlikely, there is reason for researchers, clinicians, and patients to be optimistic. Neurosurgeons are on the forefront of many of these advances and may soon be called upon to be practitioners of regenerative medicine.
脊髓損傷治療是進展很快的同時也出現很多新的視野,以及從失敗的人體試驗中學到的內容。一些受認可的治療被新的研究所調查著,不過不太可能都是毫無幫助的。雖然完全治好是不太可能,但研究者和病患還是當對研究有所期待。神經外科醫師是這些治療建議的第一線決策人員並可以考慮從事再生醫學的研究。

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