cord that results in a loss of motor control, sensory perception, bowel and bladder control, and numerous other voluntary or involuntary body functions. A traumatic blow to the spine can fracture or dislocate vertebrae, which may cause bone fragments or disc material to injure the nerve fibers and damage the oligodendrocyte cells that insulate the nerve fibers in the spinal cord. Most human spinal cord injuries are contusions (bruises) rather than lacerations to the cord.
Every year approximately 12,000 people in the United States sustain spinal cord injuries, and currently there are approximately 840,000 spinal cord injury patients in the United States. The odds of a traumatic spinal injury in the United States are 40 in 1 million, and the assessed cost of these patients is $8 billion yearly, with individual costs of up to $1.35 million over the course of one’s life. Contemporary management options give a median survival time of 38 years; however, no rehabilitative measures are available. The lack of mobility and increased dependence of SCI patients on their families or rehabilitation care aggregates psychological stress along with other secondary complications, such as urinary tract infection and pressure sores, requiring constant hospitalization, further burdening the health care system.
There are currently no approved therapies available for the treatment of spinal cord injury. Stem cells have been given attention and been under research for several years because of their remarkable ability to differentiate into neural cell lines replacing non-functional tissue. Stem cells have the ability of self-renewal and differentiation. Stem cells are first identified in the hematopoietic system; they are likely to be present in many other tissues. The care of individuals with hematologic, oncologic, dermatologic, orthopedic, or neurological diseases as well as spinal cord injury has been altered by the discovery and application of stem cells. The role of stem cells in clinical medicine can be broadly classified along at least three lines: stem cells as therapy (to replace cell lines that have been lost or destroyed), stem cells as targets of drug therapy, and stem cells to generate differentiated tissues for in vitro study of disease models for drug development.
As you will see in the following clinical trials, a number of different types of stem cells (embryonic stem cells, umbilical cord stem cells, adult neural stem cells, mesenchymal/bone marrow stem cells, etc.) are currently being studied as potential sources of neurons, glial cells, or neurotrophic factors for patients with spinal cord injury.
Spinal cord injury was the first condition targeted in a human clinical trial using cells made from embryonic stem cells. The Food and Drug Administration (FDA) approved the first clinical trial in the United States involving human embryonic stem cells on January 23, 2009, when Geron Corporation identified cells that have the potential to stimulate nerve growth and angiogenic properties leading to restoration of function in rodent models of acute spinal cord injury. These cells are derived from oligodendrocyte progenitor cells, whose function is to form myelin, which act as insulation for the axons of nerve cells in the brain and the spinal cord. These cells are named GRNOPC1.
This phase 1 trial was begun by Geron in October 2010 with financial support from the California Institute for Regenerative Medicine (CIRM). It was primarily focused on safety, and since only patients with newly onset severe injury were enrolled, it had a limited patient pool. Initially, the aim was to add 10 patients to the trial, but only four patients were enrolled, and participants received one injection of GRNOPC1 containing approximately 2 million cells. Timothy J. Atchison, Alabama resident, was identified by the Washington Post as the first patient participating in Geron’s clinical trial, and he received treatment at Shepherd Medical Center in Atlanta. Although no official results from the trial have been published yet, the Washington Post reported that after receiving treatment, Atchison began to get some slight sensation and strength in his abdomen.
Data were presented on those four patients with neurologically complete American Spinal Injury Association (ASIA) Impairment Scale grade A thoracic spinal cord injuries; GRNOPC1 was administered between 7 and 14 days after injury. Low-dose Tacrolimus (an immunosuppressive drug generally used after allogeneic organ transplant to reduce the activity of the patient’s immune system to lower the risk of organ rejection) was given for temporary immune-suppression from the time of injection for 46 days, at which point the dose was tapered and then withdrawn completely at 60 days. Although no official results from the trial have been published, preliminary results from the clinical trial were presented at the American Congress of Rehabilitation Medicine (ACRM) conference in October 2011. None of the participants experienced serious adverse events. In addition, no changes to the spinal cord or neurological condition were found.
This trial was later cancelled by Geron Corporation in November 2011 for financial reasons. By the time of the cancellation, five patients around the country had been enrolled in the study, including two at Stanford, who entered the trial during a period when CIRM funded Geron. Even though the trial has officially ended, the Geron Corporation will continue to monitor these participants for fifteen years.
In January 2013, Neuralstem Inc. received FDA approval to initiate a Phase I, open label, multi-site safety trial of human spinal cord-derived neural stem cells labelled as NSI-566 neural stem cells for chronic spinal cord injury (cSCI). This multi-site trial will enroll up to eight cSCI patients with thoracic spinal cord injuries (T2-T12) who have an American Spinal Injury Association (ASIA) grade A level of impairment one-to-two years post-injury. ASIA A impairment refers to a patient with no motor or sensory function in the relevant segments at and below the injury, and it is considered to be complete paralysis.
Prior to this approval, Neuralstem Inc. announced the publication of its preclinical data led by principal investigator Martin Marsala of the University of California, San Diego, School of Medicine, demonstrating that rats transplanted with spinal cord-derived human neural stem cells, NSI-566, three days after a spinal cord injury at L3 (lumbar 3), displayed improvement of motor function and a reduction of spasticity. Based on the promising experience of this preclinical data, this Phase I clinical study, under supervision of Neuralstem, is expected to take place at four centers in the United States. The centers taking part include University of Miami, Florida, Shepard Center in Atlanta, Georgia, Thomas Jefferson University Hospital in Philadelphia, Pennsylvania, and Medical College of Milwaukee in Wisconsin.
According to the proposed procedure, the spinal dura will be opened in mid-line and six direct injections into spinal parenchyma will be given (two bilaterally at the rostral and caudal edge of the injury site and one into about one segment length inferior to the site of injury).
Each injection in the first four subjects will consist of 1 × 105 cells in 10μL volume, while in the next four subjects each injection will consist of 2 × 105 cells in 10μL volume. The subjects will be required to remain on immunosuppressive therapy for three months both before and after the transplant procedure. They will be followed post-op at two weeks, then monthly for six months and at every six months thereafter in post-study safety follow-up for a total of 60 months. The primary objective of this trial, expected to commence in 2014, is to determine the safety and toxicity of human spinal stem cell transplantation for the treatment of paralysis and related symptoms due to cSCI. The secondary objectives of the study are to evaluate graft survival in the transplant site by MRI, as well as the effectiveness of transient immunosuppression.
Autologous stem cell transplantation is a procedure in which stem cells are removed, stored, and later given back to the same person. Children’s Memorial Hermann Hospital in Houston, Texas, which is the primary children’s teaching hospital for the University of Texas, Houston (UTHealth), has started a clinical trial of autologous stem cells for spinal cord injuries in children. The trial is in Phase 1 and currently recruiting participants who will be transplanted with their own bone marrow progenitor cells (BMPC) to assess that bone marrow cell harvest and transplantation are safe in children with spinal cord injury and also to determine if late functional outcome is improved following bone marrow cell transplantation in children with spinal cord injury using pre-transplantation spinal cord function as the control.
In 2009, results of a similar study by DaVinci Biosciences were published with
