Mansour N, and Parr AM
Spinal cord injury (SCI) research has been slowly progressing for many decades, without many clinical advances beyond early surgery and acute hospital management guidelines (Walters et al., 2013). To date, several clinical trials have been initiated in an effort to improve the lives of individuals with SCI. Yet, there remain no FDA-approved treatments that can improve neurological dysfunction after injury. Many ongoing SCI trials are still in their early stages, however a number of exciting new clinical trials for SCI are in progress, which lends hope to patients with this devastating condition. As these trials progress, researchers hope to develop groundbreaking therapeutic interventions. Upon a recent review of Clinicaltrials.gov, there are more than 1,500 clinical trials currently ongoing in approximately 46 countries. These include both trials aimed at improving the quality of life of SCI patients, and those focused on neuroprotection and/or regeneration of the spinal cord. Almost 20% of these are being conducted in the United States (US). We have chosen to highlight two important international trials because of their very different approaches, and because it is important to raise awareness of well-designed trials that are not occurring in the US, and therefore, may not be widely known by this readership.
The first trial is titled “Duroplasty for Injured Cervical Spinal Cord with Uncontrolled Swelling (DISCUS)” (ClinicalTrials.gov ID NCT04936620). The study is being conducted at St George’s, University of London over a period of 72 months. The overall concept is that opening the dura is necessary to achieve maximal spinal cord decompression. Studies in rodents have demonstrated improved functional recovery after more aggressive spinal decompression (Zhang et al., 2016), and intrathecal pressure studies in the human spinal cord after injury demonstrate elevated pressure even after bony decompression (Yang et al., 2022). Therefore, the primary aim of this study is to determine whether the addition of dural decompression to bony decompression improves muscle strength of the upper extremity in patients with acute, severe traumatic SCI. The secondary aims are to assess the functional outcomes, health-related quality of life, complication rates and mortality. The study is a prospective, double-blinded, phase III, multicenter randomized controlled trial (RCT). It aims to recruit 222 patients (Aged≥16 years) with acute, severe cervical SCI (C2 – T1), with American spinal injuries association Impairment Scale (AISA) grade A, B or C. Patients are randomized in a 1:1 ratio to undergo bony decompression alone versus bony decompression with duroplasty. Preliminary results of the study showed that the combination of laminectomy and duroplasty improves spinal cord radiological and physiological parameters compared to laminectomy alone (Phang et al., 2015). If this study is able to demonstrate the effectiveness of duroplasty in promoting clinically significant functional improvement in humans, the intervention may become the recommended treatment for cervical SCI patients, which would impact neurosurgical practice around the globe.
The second trial studies the use of induced Pluripotent Stem Cell (iPSC) derived Neural Progenitor Cells (NPCs) in subacute traumatic SCI. This study is being conducted at Keio University School of Medicine, Tokyo, Japan, and holds significant promise in the field of regenerative medicine. The overall concept of this study is that iPSC-derived NPCs have the ability to differentiate into neural cells that could integrate into the injured spinal cord, promote tissue repair and improve functional recovery. iPSCs are derived from adult human cells and can be banked. Cells can then be matched for immunological similarity between donor and recipient (much like solid organ transplantation) and the need for immunosuppression and chances of immunorejection are reduced. One of the pioneer groups exploring the use of iPSC-derived NPCs is the Okano group in Japan. This group has conducted rigorous preclinical studies to ensure the safety and efficacy of iPSC-derived NPCs and assessed various factors such as cell survival, integration into the host tissue, functionality and potential tumorigenicity (Nagoshi et al., 2020; Nagoshi & Okano, 2017). Their studies have shown promising results in improving motor function in animal models (Kajikawa et al., 2020; Kobayashi et al., 2012; Nori et al., 2011). The Okano group has recently launched the first human open-label, single-arm clinical trial involving the transplantation of iPSC-derived NPC in patients with subacute complete SCI. The cells will be prepared at Osaka National Hospital and transplanted into the site of SCI of eligible patients between the 14th and 28th day post-injury. Subsequently, the patients will be monitored for adverse events to ensure the safety of the transplanted cells. Moreover, the trial will assess potential therapeutic outcomes, such as improvements in motor and sensory function and quality of life. Future work by this group will test pharmacological drugs in human cellular models (Sugai et al., 2021). While the journey from the bench to bedside is long and challenging, the work of this group represents a significant step towards developing a novel and effective treatment for SCI.
There are several exciting ongoing and upcoming clinical trials in SCI that are the result of decades of preclinical work. The two trials highlighted here are very different, but both have real potential for paradigm changing discoveries that may significantly impact clinical practice. While DISCUS targets acute injury and neuroprotective mechanisms, the Okano trial currently targets subacute injury but may be applicable to chronic injury due to the proposed integrative and regenerative mechanisms proposed. While research on SCI has shown promising results in recent years, there is still a long way to go to transfer these interventions from the preclinical setting to routine clinical practice. These trials offer significant promise for the SCI community and the global trauma community as we eagerly await the results of ongoing trials and anticipate the launch of future studies.
References:
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NM wrote the first draft of the manuscript. AP revised the manuscript and approved its final version. All authors contributed to the conception of the manuscript.