SCI Forum Report
Update on Spinal Cord Injury Research
For more information about SCI recovery research
April 12, 2005 -The two main goals of SCI recovery research today are to "prevent secondary injury and restore function with partial regeneration," said Trent Tredway, MD , UW assistant professor of neurological surgery . "We know we don't need to effect total cure. Restoring some function will make a huge difference to patients" in terms of independence and quality of life.
A major issue influencing the development of new treatments is "Who's going to pay for this?" he said. The process of moving from animal studies in the lab to human clinical trials and FDA approval is long and expensive. Tredway believes much of the funding will come from the companies that are now developing new treatments.
Already, cost has played a role in focusing research on the acute rather than chronic phase. An experimental procedure such as a stem cell injection can be easily and inexpensively "piggybacked" onto the stabilization surgery done immediately post-injury (and covered by insurance), whereas a new surgical procedure for the sole purpose of conducting an experimental treatment is harder to justify and fund. Many people with long-time injuries understandably find the focus on acute therapies frustrating. However, Tredway believes that once treatments are developed for acute injuries, "it shouldn't be much of a leap to apply them to more chronic patients."
FDA approval of new treatments involves a three-phase clinical trial process. In phase I, about 20-80 subjects are given the treatment to determine safety, dosage range and side effects. In phase II, the study is expanded to 100-300 subjects to determine if the treatment is effective and safe. Phase III is "the golden phase," Tredway said, and involves 1000-3000 participants at multiple sites, "to confirm effectiveness, monitor side effects, compare it to other standard treatments, and collect information regarding safety."
There are several avenues of research that Tredway believes show promise and may eventually lead to successful treatments for SCI. Oscillating Field Stimulation (OFS ), 1 , 2 , 3 which uses a small, continuously applied electrical field, has been shown to stimulate growth of frog and mammalian neurons, and results of a phase I trial in humans have been positive. 4 Ten patients whose injuries were classified as complete (ASIA A) 48 hours after injury received OFS one level above and one level below the lesion while undergoing initial stabilization surgery. The OSF continued for 15 weeks. Results showed statistically significant improvement in sensory and motor scores in subjects who had the procedure, compared to patients in a national database who didn't get the procedure. But this was not a "true control," Tredway said, so it's not possible to determine if the improvement was a result of the treatment or would have occurred naturally, since many people improve in the days and weeks following injury. This study showed the procedure is safe, and it is now awaiting phase II clinical trial.
Studies using activated macrophages to promote spinal cord repair are currently in phase II clinical trials in the U.S. 5 Proneuron Biotechnologies developed this procedure, called ProCord , based on research conducted in Israel by Dr. Michal Schwartz.
Macrophages are a type of white blood cell that helps remove debris and heal tissue after injury. While these cells are active in peripheral nerves, they are limited in the central nervous system (CNS). The ProCord process collects macrophages from the patient's own blood, activates it, and injects the cells into the spinal cord at the site of the injury. Phase I trials in Israel involving ten patients demonstrated safety and some promise. Phase II trials are currently under way in the U.S.
Embryonic stem cells in spinal cord repair-a highly politicized topic today-are important because "they can give rise to all neural progenitors," Tredway explained, meaning they have the potential to turn into any type of cell under the right conditions (a quality referred to as "pluripotent"). Research by John McDonald, MD, PhD, has demonstrated the potential of these cells in SCI repair using animal models. 6 ( Click here to download Dr. McDonald's article as a PDF file . )
Bone marrow stromal cells (BMSCs ) also have been shown to have pluripotent capabilities. In rat studies in Japan, BMSCs injected into the cerebrospinal fluid (CSF) improved CNS regeneration. 7
In other studies, gene-modified neural progenitor cells (NPCs) were genetically altered to develop into a variety of neural cells. 8 , 9 NPCs intravenously injected into rats 24 hours after injury differentiated into several different neural cells, migrated to the lesion, and survived for at least 56 days after IV injection. "That's a long time to survive," Tredway said. "These results are pretty impressive. IV administration is much simpler and cheaper (than surgery)."
Glial cells -supportive cells that nourish and protect neurons-have been the focus of several studies. Glial-restricted precursor cells (a precursor cell population restricted to oligodendrocytes and astrocyte lineages) transplanted into rat spinal cords have been found to alter the growth of CSF axons and may support axonal growth after injury. 10
Olfactory ensheathing cells from the patient's own olfactory (nasal) mucosa have been shown to reduce scar and cavity formation as well as promote regeneration after SCI. The work was carried out in mice and rats, and there are now efforts to bring this to human trial. 11
One study has demonstrated the feasibility and safety of neural transplantation in SCI patients with syringomyelia. 12 The Geron Corporation, which has several stem cell lines (acquired prior to current restrictions), is planning Phase I trials in acute ASIA A SCI patients six-to-ten days after injury. Tredway hopes to participate in these trials here at the UW.
Phil Horner, PhD, UW assistant professor of neurological surgery, demonstrated that there are stem cells within the adult spinal cord capable of giving rise to glial cells, 13 suggesting "a higher level of cellular plasticity for the intact spinal cord than previously observed," Tredway said. "This is a very important step" toward finding alternatives to embryonic stem cells. (Click here to download Dr. Horner's article as a PDF file.) [colleen-this article is Horner Paper.pdf]
Tredway believes spinal cord repair will likely involve a combination of several biomedical technologies and modalities. "Technology changes rapidly, and we are just starting to hit our stride in the area of SCI," he said. "The future is now." As long as adequate funding is pumped into stem cell research, "It won't take 20-30 years."
1 . Borgens RB, Shi R. Uncoupling histogenesis from morphogenesis in the vertebrate embryo by collapse of the transneural tube potential. Dev Dyn . 1995 Aug;203(4):456-67.
2 . Hinkle L, McCaig CD, Robinson KR. The direction of growth of differentiating neurones and myoblasts from frog embryos in an applied electric field. J Physiol. 1981 May;314:121-35.
3 . McCaig CD. Spinal neurite reabsorption and regrowth in vitro depend on the polarity of an applied electric field. Development . 1987 May;100(1):31-41.
4 . Shapiro S, Borgens R, Pascuzzi R, et al. Oscillating field stimulation for complete spinal cord injury in humans: a phase 1 trial. J Neurosurg Spine . 2005 Jan;2(1):3-10.
5 . Rapalino O. et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med. 1998 Jul;4(7):814-21.
6 . McDonald JW, Becker D, Holekamp TF, et al. Repair of the injured spinal cord and the potential of embryonic stem cell transplantation. J Neurotrauma . 2004 Apr;21(4):383-93. Review. [please add link to pdf file here too]
7 . Ohta M, Suzuki Y, Noda T, et al. Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation. Exp Neurol. 2004 Jun;187(2):266-78.
8 . Setoguchi T, Nakashima K, Takizawa T, et al. Treatment of spinal cord injury by transplantation of fetal neural precursor cells engineered to express BMP inhibitor. Exp Neurol. 2004 Sep;189(1):33-44.
9 . Fujiwara Y, Tanaka N, Ishida O, et al. Intravenously injected neural progenitor cells of transgenic rats can migrate to the injured spinal cord and differentiate into neurons, astrocytes and oligodendrocytes. Neurosci Lett . 2004 Aug 19;366(3):287-91.
10 . Hill CE, Proschel C, Noble M, et al. Acute transplantation of glial-restricted precursor cells into spinal cord contusion injuries: survival, differentiation, and effects on lesion environment and axonal regeneration. Exp Neurol . 2004 Dec;190(2):289-310.
11 . Ramer LM, Au E, Richter MW, et al. Peripheral olfactory ensheathing cells reduce scar and cavity formation and promote regeneration after spinal cord injury. J Comp Neurol. 2004 May 17;473(1):1-15.
12 . Thompson FJ, Reier PJ, Uthman B, et al. Neurophysiological assessment of the feasibility and safety of neural tissue transplantation in patients with syringomyelia. J Neurotrauma . 2001 Sep;18(9):931-45.
13 . Horner PJ, Power AE, Kempermann G, et al. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. J Neurosci . 2000 Mar 15;20(6):2218-28. [please add link to pdf file here too]
For more information about SCI recovery research:
. The Reeve-Irvine Research Center , University of California at Irvine, 2109 Gillespie Neuroscience Research Facility, Irvine, CA, 92697; 949-824-3993; mhofstad@uci.edu ; www.reeve.uci.edu/infoabout
. Spinal Cord Society. 19051 County Highway 1, Fergus Falls, Minnesota 56537; 218-739-5252 http://members.aol.com/scsweb/ ; Northwest Chapter : PO Box 6092, Edmonds, WA 98026; 425-670-2622; scsnnwgolf@aol.com ; www.scsnw.com/
. CareCure Community , W. M. Keck Center for Collaborative Neuroscience, State University of New Jersey, Rutgers. http://carecure.org
. The Miami Project to Cure Paralysis, University of Miami School of Medicine; 800-STANDUP; www.miamiproject.miami.edu/