Cells are implanted into the damaged spinal cord by direct injection. There are several variables to consider in the development of a safe injection method. Transplant injections have the potential to create damage to preserved spinal tissue in several ways and associated injury must be minimized. The most damaging injections are those of large volumes, delivered rapidly, with poor control over motion of the needle and tissue interface . In the clinical environment, it is important to consider all contingencies that might add risk during the cellular transplantation because unpredictable events such as, for example, electrical power failure or anesthetic emergencies, including cardiopulmonary instability, although uncommon, do occur. Therefore, the ability to terminate the injection and exit the spinal cord rapidly is necessary. A rigid needle within spinal cord tissue can cause serious injury if there is loss of control of the position of the needle because of operator error, injection device dysfunction, or inadvertent patient motion. Currently, there are three main approaches to make spinal cord injections: free hand needle injections, fixed platform injections, and floating cannula injections [47,48]. Each method has specific merits and limitations. We currently use a fixed platform injection apparatus.
Selecting the optimal clinical cell dose is a challenging task because of the complex effects of cells compared to more conventional drugs. For example, after most cell injections, some cells will die and engender some degree of inflammation. Thus, both beneficial and harmful events may occur simultaneously after transplantation. The best cell dose is a function of the final result in the tissue and may not be based solely on a single tissue effect. There is a limited ability to monitor toxicological endpoints in SCI patients receiving cell transplants other than worsening of the neurological injury density or level. Complications of SCI such as neuropathic pain and spasticity occur to some extent in most patients and linking these endpoints to the cell dose may be difficult. The formation of abnormal tissue or tumors may occur independent of the cell dose. In our IND development, we have focused on learning the maximum tolerated dose that can be delivered to the spinal cord in animals and not cause additional injury that is evident by clinical examination, neurophysiology, postinjection MRI, or histology. We found that the minipig SCI model was very useful for dose tolerance studies because of its human-like neural axis dimensions. On the basis of large animal testing, we determined a well tolerated dose at which to initiate the study and successive larger doses that may exert a superior therapeutic effect.
In our current study, the most important outcomes are the feasibility of the autologous transplant strategy and the safety of the procedures and cellular implant. Impairment of residual neurological function could occur as a result of the surgical implantation procedure or because of the biological effect of the cell transplant. In patients with complete thoracic SCI, such changes are measured using sensory testing, with the neurological level as the endpoint. This level is defined as the last at which sensory perception is normal on both sides. The outcome measures we are utilizing are listed in Table 3[5–7].
It is desirable to have clinical tests that allow the effect of cell implantation to be followed longitudinally, especially to determine cell survival and biological activity. This is important because a clear impact on neurological recovery may not occur with cell grafts alone and will likely require future combination therapies. The paucity of surrogate markers is not unique to Schwann cell transplantation, but is a general problem facing the CNS cell therapy field. The doses of transplanted cells are relatively small compared with the overall cell death that occurs after SCI, potentially masking the ability to detect Schwann-cell-specific markers of cell death and survival. For Schwann cells, the issue is further complicated because of the fact that endogenous Schwann cells enter the regions of SCI and may have similar biological activity. Because allografts require immune suppressive drugs to avoid cellular rejection, formation of antiallograft antibodies is a useful biomarker that is not available for autografts to determine a definite host response. It is likely that progress in this area will require the development of well tolerated molecular markers that the transplanted cells can uniquely express and which do not impair their biological activity in the long term.
Autologous Schwann cell transplantation is a reasonable treatment approach to the repair of spinal cord injuries based on the role of Schwann cells in peripheral nerve repair, the endogenous Schwann cell's response to spinal cord injury, and the feasibility of preparing and delivering the cells. More clinical experience is required to determine the safety and efficacy. It is probable that future studies will combine Schwann cell transplantation with additional therapies to amplify the reparative effects.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1▪. Arthur-Farraj PJ, Latouche M, Wilton DK, et al. c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 2012; 75:633–647.
An important molecular study that shows that c-Jun expression is the key event that causes Schwann cells to dedifferentiate into a repair phenotype.
2. Mirsky R, Jessen KR. The neurobiology of Schwann cells. Brain Pathol 1999; 9:293–311.
3. Howell WH, Huber GC. A physiological, histological and clinical study of the degeneration and regeneration in peripheral nerve fibres after severance of their connections with the nerve centres. J Physiol 1892; 13:335–406.311.
4. Bunge MB, Wood PM. Realizing the maximum potential of Schwann cells to promote recovery from spinal cord injury. Handb Clin Neurol 2012; 109:523–540.
5. Saberi H, Moshayedi P, Aghayan HR, et al. Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett 2008; 443:46–50.
6. Saberi H, Firouzi M, Habibi Z, et al. Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases. J Neurosurg Spine 2011; 15:515–525.
7. Zhou XH, Ning GZ, Feng SQ, et al. Transplantation of autologous activated Schwann cells in the treatment of spinal cord injury: six cases, more than five years of follow-up. Cell Transplant 2012; 21 (Suppl. 1):S39–S47.
8. Aghayan HR, Arjmand B, Norouzi-Javidan A, et al. Clinical grade cultivation of human Schwann cell, by the using of human autologous serum instead of fetal bovine serum and without growth factors. Cell Tissue Bank 2012; 13:281–285.
9. Eaton DA, Hirsch BE, Mansour OI. Recovery of facial nerve function after repair or grafting: our experience with 24 patients. Am J Otolaryngol 2007; 28:37–41.
10. Garozzo D, Ferraresi S, Buffatti P. Surgical treatment of common peroneal nerve injuries: indications and results. A series of 62 cases. J Neurosurg Sci 2004; 48:105–112.discussion 112.
11. Trumble TE, Vanderhooft E, Khan U. Sural nerve grafting for lower extremity nerve injuries. J Orthop Trauma 1995; 9:158–163.
12. Wood MB. Peroneal nerve repair. Surgical results. Clin Orthop Relat Res 1991; 267:206–210.
13. Levi AD, Guenard V, Aebischer P, Bunge RP. The functional characteristics of Schwann cells cultured from human peripheral nerve after transplantation into a gap within the rat sciatic nerve. J Neurosci 1994; 14:1309–1319.
14. Levi AD, Sonntag VK, Dickman C, et al. The role of cultured Schwann cell grafts in the repair of gaps within the peripheral nervous system of primates. Exp Neurol 1997; 143:25–36.
15. Guest JD, Rao A, Olson L, et al. The ability of human Schwann cell grafts to promote regeneration in the transected nude rat spinal cord. Exp Neurol 1997; 148:502–522.
16. Xu XM, Guenard V, Kleitman N, Bunge MB. Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J Comp Neurol 1995; 351:145–160.
17. Fishman PS, Nilaver G, Kelly JP. Astrogliosis limits the integration of peripheral nerve grafts into the spinal cord. Brain Res 1983; 277:175–180.
18. Richardson PM, McGuinness UM, Aguayo AJ. Axons from CNS neurons regenerate into PNS grafts. Nature 1980; 284:264–265.
19. Smith GV, Stevenson JA. Peripheral nerve grafts lacking viable Schwann cells fail to support central nervous system axonal regeneration. Exp Brain Res 1988; 69:299–306.
20. Brockes JP, Fields KL, Raff MC. Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve. Brain Res 1979; 165:105–118.
21. Casella GT, Bunge RP, Wood PM. Improved method for harvesting human Schwann cells from mature peripheral nerve and expansion in vitro. Glia 1996; 17:327–338.
22. Levi AD, Bunge RP, Lofgren JA, et al. The influence of heregulins on human Schwann cell proliferation. J Neurosci 1995; 15:1329–1340.
23. Hilton DA, Jacob J, Househam L, Tengah C. Complications following sural and peroneal nerve biopsies. J Neurol Neurosurg Psychiatry 2007; 78:1271–1272.
24. Fraher JP. The transitional zone and CNS regeneration. J Anat 2000; 196 (Pt 1):137–158.
25. Fraher JP. The transitional zone and CNS regeneration. J Anat 1999; 194 (Pt 2):161–182.
26. Duncan ID, Hammang JP, Gilmore SA. Schwann cell myelination of the myelin deficient rat spinal cord following X-irradiation. Glia 1988; 1:233–239.
27. Bruce JH, Norenberg MD, Kraydieh S, et al. Schwannosis: role of gliosis and proteoglycan in human spinal cord injury. J Neurotrauma 2000; 17:781–788.
28. Guest JD, Hiester ED, Bunge RP. Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp Neurol 2005; 192:384–393.
29. Kanakis DN, Kamphausen T, Van de Nes J. A 32-year-old male with brainstem lesions. Brain Pathol 2013; 23:101–104.
An important update on FDA's expectations for preclinical data to support cellular therapy clinical trials.
31. Bosse R, Kulmburg P, von Kalle C, et al. Production of stem-cell transplants according to good manufacturing practice. Ann Hematol 2000; 79:469–476.
32▪▪. Lammertse DP, Jones LA, Charlifue SB, et al. Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial. Spinal Cord 2012; 50:661–671.
The first reported study of cell therapy in acute spinal cord injury.
33▪▪. Grossman RG, Frankowski RF, Burau KD, et al. Incidence and severity of acute complications after spinal cord injury. J Neurosurg Spine 2012; 17:119–128.
An important multicentre prospective study that provides baseline data to anticipate the incidence and type of complications following acute spinal cord injury.
34. Zariffa J, Kramer JL, Fawcett JW, et al. Characterization of neurological recovery following traumatic sensorimotor complete thoracic spinal cord injury. Spinal Cord 2011; 49:463–471.
35. Alper J. Geron gets green light for human trial of ES cell-derived product. Nat Biotechnol 2009; 27:213–214.
36. Frantz S. Embryonic stem cell pioneer Geron exits field, cuts losses. Nat Biotechnol 2012; 30:12–13.
37. Lebkowski J. GRNOPC1: the world's first embryonic stem cell-derived therapy Interview with Jane Lebkowski. Regen Med 2011; 6:11–13.
38. Wirth E3rd, Lebkowski JS, Lebacqz K. Response to Frederic Bretzner et al.
Target populations for first-in-human embryonic stem cell research in spinal cord injury. Cell Stem Cell 2011; 8:476–478.
39▪▪. Glass JD, Boulis NM, Johe K, et al. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells 2012; 30:1144–1151.
The first completed study of neural stem cells transplanted into the human spinal cord.
40. Riley J, Federici T, Polak M, et al. Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I safety trial, technical note, and lumbar safety outcomes. Neurosurgery 2012; 71:405–416.discussion 416.
41. Stradiotti P, Curti A, Castellazzi G, Zerbi A. Metal-related artifacts in instrumented spine. Techniques for reducing artifacts in CT and MRI: state of the art. Eur Spine J 2009; 18 (Suppl. 1):102–108.
42. Mann R, Schaefer C, Sadosky A, et al. Burden of spinal cord injury-related neuropathic pain in the United States: retrospective chart review and cross-sectional survey. Spinal Cord 2013; 51:564–570.
43. Margot-Duclot A, Tournebise H, Ventura M, Fattal C. What are the risk factors of occurrence and chronicity of neuropathic pain in spinal cord injury patients? Ann Phys Rehabil Med 2009; 52:111–123.
44. Macias MY, Syring MB, Pizzi MA, et al. Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol 2006; 201:335–348.
45. Monje PV, Soto J, Bacallao K, Wood PM. Schwann cell dedifferentiation is independent of mitogenic signaling and uncoupled to proliferation: role of cAMP and JNK in the maintenance of the differentiated state. J Biol Chem 2010; 285:31024–31036.
46. Guest J, Benavides F, Padgett K, et al. Technical aspects of spinal cord injections for cell transplantation. Clinical and translational considerations. Brain Res Bull 2011; 84:267–279.
47. Federici T, Hurtig CV, Burks KL, et al. Surgical technique for spinal cord delivery of therapies: demonstration of procedure in Gottingen minipigs. J Vis Exp 2012; 70:e4371.
48. Riley JP, Raore B, Taub JS, et al. Platform and cannula design improvements for spinal cord therapeutics delivery. Neurosurgery 2011; 69:ons147–ons154.discussion ons155.