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Clinical Trials Outside the United States: Spinal Cord Injury

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Clinical Trials Outside the United States: Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition that causes significant morbidity and mortality. Spinal cord injury can occur anywhere between the neck and the lower back. SCI mostly affects young adults, and motor vehicle accidents alone account for more than 50 percent of the SCI cases. Other causes include sporting accidents, serious falls either at work or at home, wounds, and diseases of the spine such as spina bifida.

The estimated annual global incidence of spinal cord injury is 15 to 40 cases per million. In North America, approximately more than a million individuals live with a disability as a result of spinal cord injury and half of those are quadriplegic, with the paralysis impacting all four limbs to some extent. For those individuals, the lifetime cost of managing their condition and other injury-related expenses is estimated to be between $2 million and $3 million and can reach up to $25 million.

Laceration, contusion, compression, and concussion are hallmarks of the primary injury caused by the initial physical and/or mechanical trauma to the spinal cord. Subsequently, secondary injury giving rise to ischemia, microvascular damage, glutamatergic excitotoxicity, oxidative stress, and inflammation set in further damages to the nerves, leading to formation of a glial scar and paralysis below the site of lesion. Though complete transection of the spinal cord is rare, residual connections usually persist after injury, indicating potential for recovery. Considering the gravity of the medical condition, spinal cord injury has been the main focus of advanced medical research for the past few years and continuous efforts have been made to establish new synapses and provide an appropriate growing environment to already injured parts of the spinal cord.

In recent years, the exciting discovery of neural stem cells derived from adults or embryos has shown great promise as a potential source of neural cells for regenerative therapies. Scientists and researchers around the world are involved in continuing experiments to develop culture systems and drugs that can direct stem cell differentiation in animal models of spinal cord injury.

Stem cell transplantation for SCI has been at the forefront for quite some time now, with animal and in vitro studies providing a solid platform to enable well-designed human studies. Based on the results of past successful preclinical studies, olfactory ensheathing cells seem to be the most promising, whereas bone marrow stromal cells (BMSC) also seem to be strong promising candidates for an adjunctive role.

In clinical trials on stem cell transplantation in spinal cord injury involving animal models, a conclusive meta-analysis and systemic review was done by a team of authors from Australia and the United Kingdom in which they included the data from controlled in vivo studies testing the efficacy of stem cells as a treatment in animal models of traumatic spinal cord injury. In this meta-analysis of 156 publications, the outcomes were reported and compared on a scale of effect size (percentage improvement in motor score and sensory score).

According to this systemic review and meta-analysis, overall allogeneic stem cell treatment in spinal cord injury in animals appears to improve motor function by 27.2 percent and sensory function by 26.3 percent, depending on stem cell dose, its derivation (adult or embryonic), manipulation in culture (genetic, antibiotic, growth factor), number of passages in culture, method of stem cell selection prior to implantation, route of administration, frequency of administration, the presence or absence of a supporting scaffold, time of assessment, anesthetic used, and temperature regulation during surgery.

An injury to the spinal cord can disrupt the cord’s normal motor, sensory, or autonomic function and can be either temporary or permanent. Most often traumatic, spinal cord injuries can include the cervical (neck), thoracic (arms or hands) and/or lumbosacral (legs) regions of the body.

Human bone marrow cells have long been studied by scientists in the treatment of hematologic diseases. Moreover, some studies have found out that bone marrow cells can be differentiated into neurons and glial cells when induced under experimental conditions. In recent years, transplantation of autologous bone marrow transplantation as a potential source of progenitor cells in patients with spinal cord injury has been studied in clinical trials around the world. In Hospital São Rafael, Salvador, Brazil, Ricardo dos Santos and his team initiated a Phase I clinical trial in July 2010 that is investigating the feasibility and safety of autologous bone marrow stem cell transplantation in patients with spinal cord injury. Likewise, Andrés Chahín and his team are conducting a phase II clinical trial in Clínica Las Condes, Santiago, Chile, to evaluate the use of autologous expanded mesenchymal stem cells intralesional transplantation as a safe and potentially beneficial treatment for patients with spinal cord injury. The research team believes that this study will provide more data on the potential improvement of sphincter controls and muscular strength with the transplantation of mesenchymal stem cells.

In December 2010, StemCells Inc. received authorization from Swissmedic, the Swiss regulatory agency for therapeutic products, to initiate a phase I/II clinical trial of its HuCNS-SC product (human neural stem cells) in patients with spinal cord injury. This interventional study was initiated at Balgrist University Hospital, University of Zurich and is being chaired by Stephen Huhn and his team in Zurich, Switzerland. This Phase I/II clinical trial will evaluate the safety and preliminary effects of single intramedullary transplantation of HuCNS-SC into the thoracic spinal cord of patients with subacute spinal cord injury. This clinical trial was initiated in March 2011 and its estimated completion date is March 2016.

To date, no official results have been issued, but data from three patients who completed the trial in December 2012 showed that two patients displayed some multi-segment gains in sensory function 12 months post transplantation of HuCNS-SC. One of these two patients converted from a complete injury classification to an incomplete injury, while the third patient remained stable. The research team believes that the study has given an excellent safety profile and encouraging results to date and they have amended the research protocol to allow continued enrollment of patients with complete injury in addition to patients with less severe or incomplete injury.

Based on this safety profile, on June 3, 2013, Health Canada authorized StemCells Inc. to expand its clinical trial into Canada. Following the approval, a team of doctors headed by Steven Casha at the University of Calgary successfully performed a stem cell transplant in an SCI patient in January 2014. Neural stem cells were injected into the spine of a 29-year-old paraplegic male, who will now be monitored to determine whether implanting those cells is safe. At present (2014), StemCells Inc. has nine patients enrolled in this study and plans to enroll 12 more subjects who have been paralyzed from the chest down. Apart from the Balgrist University Hospital in Zurich, Switzerland, and University of Calgary, patients are being enrolled at the University of Toronto (UT) with Michael Fehlings, head of the spinal program at Toronto Western Hospital, as the lead investigator for the trial at UT.

After obtaining Food and Drug Administration (FDA) approval to initiate a Phase I, multisite safety trial of the human spinal cord–derived neural stem cell labeled NSI-566 neural stem cells for chronic spinal cord injury (cSCI) in the United States, Neuralstem is also seeking to study NSI-566 in patients with acute SCI. For this purpose, a phase 1/2 study is expected to commence in 2014 in Seoul, South Korea, in collaboration with partner CJ CheilJedang. The trial will be similar in design to the chronic SCI trial being carried out in the United States, only enrolling 8 to 10 patients with acute injury hours after the traumatic event.

Stem cell therapy does offer a glimmer of hope to patients whose injuries have long been considered untreatable. Can stem cell therapy potentially enhance the quality of life of those affected by SCI? This still remains to be proven in humans. Though the answer seems to be a long way ahead right now, it is essential nonetheless for people with spinal cord injuries to know that there is potential hope on the horizon and that there are efforts under way right now to move forward toward a possible cure.

Syed A. Quadri

Desert Regional Medical Center, Palm Springs

Shariq Nawab

Sajid S. Suriya

Fahad Mehmood

Dow University of Health Sciences

Muhammad Junaid Uddin Zaheer

Aga Khan University Hospital

See Also: Adult StemCells: Overview; Bone Marrow Transplants; Canada: Stem Cell Network; Clinical Trials, U.S: Spinal Cord Injury; Neuralstem, Inc.; Spinal Cord Injury; Swiss Stem Cells Network; University of Toronto.

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Clinical Trials Outside the United States: Spinal Cord Injury

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