Spinal cord clinical trials and the role for bioengineering

Neuroscience Letters 519 (2012) 93–102

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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet

Review

Spinal cord clinical trials and the role for bioengineering Jared T. Wilcox a,b , David Cadotte a,c , Michael G. Fehlings a,b,c,∗ a

Institute of Medical Science, University of Toronto, Toronto, Canada M5S 1A8 Division of Genetics and Development, Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Canada M5T 2S8 c Department of Surgery, Division of Neurosurgery, Toronto Western Hospital, Toronto, Canada M5T 2S8 b

a r t i c l e

i n f o

Article history: Received 2 February 2012 Accepted 8 February 2012 Keywords: Spinal cord injury Clinical trials Bioengineering Cell therapy Environmental modification

a b s t r a c t There is considerable need for bringing effective therapies for spinal cord injury (SCI) to the clinic. Excellent medical and surgical management has mitigated poor prognoses after SCI; however, few advances have been made to return lost function. Bioengineering approaches have shown great promise in preclinical rodent models, yet there remains a large translational gap to carry these forward in human trials. Herein, we provide a framework of human clinical trials, an overview of past trials for SCI, as well as bioengineered approaches that include: directly applied pharmacologics, cellular transplantation, biomaterials and functional neurorehabilitation. Success of novel therapies will require the correct application of comprehensive preclinical studies with well-designed and expertly conducted human clinical trials. While biologics and bioengineered strategies are widely considered to represent the high potential benefits for those who have sustained a spinal injury, few such therapies have been thoroughly tested with appreciable efficacy for use in human SCI. With these considerations, we propose that bioengineered strategies are poised to enter clinical trials. © 2012 Elsevier Ireland Ltd. All rights reserved.

Contents 1.

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5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Targeting therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Treating spinal injury: history and clinical challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conducting human trials for SCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Framework of human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Focusing trials for SCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current state of SCI therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Landscape of current trials and clinical treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Improving therapeutic options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SCI trials: pharmacologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Lessons learned from early trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Ion channel blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Emergence of directed pharmacologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cell transplantation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Preclinical success . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Non-neural stem cells: macrophage, BMSC and UCB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Peripheral myelinating cells: OEC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Pluripotent cells: Geron trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Adapting successful trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94 94 94 94 94 95 95 95 95 96 96 96 96 97 97 97 98 98 98

Abbreviations: ASIA, American Spinal Injury Association; AIS, ASIA Impairment Scale; ESC, embryonic stem cell; FES, functional electrical stimulation; FIM, functional independence measure; MPSS, methylprednisolone sodium succinate; NACTN, North American Clinical Trials Network; NASCIS, National Acute Spinal Cord Injury Study; NCT, National Clinical Trials database; NPC, neural precursor cell; OEC, olfactory ensheathing cell; OPC, oligodendrocyte progenitor cell; RCT, randomized controlled trial; SCI, spinal cord injury; SCIM, spinal cord independence measure; UCB, umbilical cord blood. ∗ Corresponding author at: The Krembil Neuroscience Center, Rm 12-McL407, 399 Bathurst St., Toronto Western Research Institute, Toronto, Ontario, Canada M5T2S8. Tel.: +1 416 603 5800x5229; fax: +1 416 603 5298. E-mail addresses: [email protected], [email protected], [email protected] (M.G. Fehlings). 0304-3940/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2012.02.028

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Bioengineered strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Electrical stimulation for neuroplastic repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Environmental modification and biomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Considerations for future clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Closing remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Knowledge of the pathophysiology and mechanisms underlying spinal cord injury (SCI) has increased greatly in recent decades due to prolific preclinical research. Advances in the basic understanding of SCI have allowed significant exploration into various therapeutic strategies for the treatment of spinal injuries (see recent systematic reviews [70,71,116]). Surgical and medical management of SCI has also seen significant advances [34], greatly increasing the survival of spinal injured persons, which will likely inform the application of novel regenerative medicines. Despite these advances and the success of several putative treatments in rodent models of SCI, a considerable translational gap remains [69]. Few recently developed biologics and bioengineered strategies are poised to cross the translational gap and enter the clinic. There has been a recent emergence of novel clinical trials in SCI, such as cell transplantation therapy, albeit with considerable difficulties. This review aims to provide a meaningful overview of the current status of human trials for SCI, the bioengineered therapeutics poised for human application, and the proper framework needed to close the interceding translational gap. Considerations for future clinical trials will also be addressed, as informed by the recent tribulations of cancelled clinical trials. For comprehensive discussions on preclinical animal data and human clinical trials for SCI, please refer to corresponding articles within this issue and reviews elsewhere [71,113,116]. 1.1. Targeting therapy Spinal injuries involve a primary physical injury and a secondary subsequent physiological cascade that disrupts motor, sensory and autonomic functions [30,114]. These secondary sequelae can include cardiac output, vascular tone, and respiratory functions, which pose a high risk of morbidity and mortality [103]. Understanding the mechanisms of injury is crucial for developing therapeutic interventions and avoiding potential adverse consequences. Endogenous repair and regenerative mechanisms are employed during the secondary phase of injury to minimize the extent of the lesion, to clear cellular debris, to reorganize the blood supply through angiogenesis, to form protective barriers (scarring) through astrogliosis, reunite local synaptic connections (anatomical plasticity) and to remodel damaged neural circuits (connective plasticity) [98]. These endogenous processes offer exploitable targets for therapy, and can be thought of in terms of their reparative process, or the temporal injury progression through: immediate (minutes to hours), acute (hours to days), subacute (days to weeks), and chronic (months to years) phases of SCI. Putative therapy should address one or more of these injury phases, with corresponding therapeutic targets of: (1) minimizing acute cell loss, (2) promoting sustained neuroprotection, (3) permissive tissue modification, and/or (4) functional neuroplasticity and regeneration (see Fig. 1). 1.2. Treating spinal injury: history and clinical challenges Medical and surgical management of patients incurring spinal injuries has advanced greatly. Presentation with traumatic spinal

99 99 99 99 99 99

injury long remained a condition not to be treated; however, surgical management improved around the Second World War, with the development of posterior stabilization and surgical decompression [55]. While peri-injury management has proven increasingly difficult, early surgical decompression, aggressive medical management and comprehensive imaging have advanced the standards of care [34]. While much preclinical data exists, the majority of which is in thoracic rodent models, there is great discrepancy in the clinical community about what preclinical data is required to take potential therapy into human trials [69]. There are examples of large prospective, controlled multicenter studies that have shown some neurological benefit, however, such as early surgical decompression and potential for corticosteroids with STASCIS [36] and NASCIS trials, respectively [6]. Recent clinical trials have evaluated corticosteroids, directly applied biologics and cell-based therapy in SCI. These trials have engendered much controversy, however, the issues raised are as much related to the current landscape of clinical trials in SCI as the therapy themselves.

2. Conducting human trials for SCI 2.1. Framework of human studies Clear and thorough guidelines have been recently formed for conducting human trials involving patients with SCI. This framework has been defined by large collaborative efforts on the basis of clinical trial design [72], outcome measures [108] and suitable patient populations [32,118]. The premature suspension or cancellation of the first clinical trials involving directed cell transplantation therapy for SCI (see below) has underscored the importance of these considerations before moving into arduous and costly studies [83,97]. The Ottawa Statement and Declaration of Helsinki propose clear and well-regarded guidelines on the registration, operation, and reporting of global human clinical trials [105]. Despite some deliberations, the proposed guidelines have been largely accepted by the NIH, CIHR, WHO, and others internationally [26,68]. Most countries having begun legislation in this new phase of medical research with human participants, such as the Fair Access to Clinical Trials Act, a pending legislation before the U.S. Congress first proposed in 2005. Registration of clinical trials is a key issue, best posed by the International Clinical Trials Registry Platform (ICTRP), and a priori necessary by the International Committee of Medical Journal Editors (ICMJE) for publication [25]. Conversely, uncontrolled trials (i.e. without concurrent untreated/comparison group) and patient studies are not governed by these regulations or legislation and may operate outside such standards. Industry and public institutes have slowly conformed to these standards and transparencies [68,95]; however, data reported in the registry is often incomplete, changed, or inaccurate [56]. Registry and reporting is necessary to recovery from the mistrust caused by recent clinical trials scandals [15,105], and move forward with public and governmental support.

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Fig. 1. Pathophysiology of spinal cord injury and approaches of bioengineered therapies. Spinal cord injuries involve a lesion consisting of considerable cell loss with inflammatory necrosis and glial scarring. Loss of oligodendrocytes results in dysmyelination and axonal dieback. Inhibitory cues such as degraded myelin (purple debris) block regeneration, synaptic plasticity and recovery of function. Major approaches of bioengineered therapies include: (1) neuroprotection to reduce cell loss, (2) removal of Inhibition to allow functional regeneration, (3) environmental modification to reduce glial scarring, (4) cell replacement to remyelinate denuded axons, and (5) enhancing neural plasticity to recover lost function.

2.2. Focusing trials for SCI Trialists must strike a balance when designing a study such that it is least likely to cause harm during phase I/II, and demonstrate possible efficacy in phases II and III. With regard to spinal cord injury, this balance is determined by the choice of which patient categories are to be included: cervical vs. thoracic, subacute vs. chronic, and complete (AIS A) vs. incomplete (AIS B–D) SCI. Traumatic and non-traumatic SCI are sustained in the cervical cord at an incidence of >60% [1,67,103,127]. Cervical SCI increases in countries and regions with more motor vehicle collisions and violence [22,78,103] to represent up to 76% of all SCI. Lifespan changes in SCI are also know, with greater SCIWORA, non-fracture and highcervical (C2–C4) SCI occurring in adolescent populations [86]. In the aged population, the incidence of non-traumatic, incomplete and cervical SCI rises sharply (mainly due to falls) [31,58]. Annual total incidence of SCI ranges from 12 to 71 per million population [67,78,127,129], typically underestimated due to pre-hospital mortality exclusion [103], with an approximated 700 ± 500 per million living with SCI worldwide [22,103,128,129]. While the initial clinical trials included patients with complete (AIS A), subacute, thoracic injury, future trials should begin addressing the largest patient populations of SCI (i.e. incomplete, chronic, and cervical SCI). 3. Current state of SCI therapy 3.1. Landscape of current trials and clinical treatment Despite the modest therapeutics that can be used to treat SCI, there are currently 386 clinical trials registered with clinicaltrials.gov, the only database conforming to ICMJE and ICTRP standards (Table 1). Of these registered trials, a subset of 48 (12%), 21 (5%) and 16 (4%) involve studying the effects of electrostimulation, repairdirected pharmacologics and cell transplantation, respectively. With the exception of physical rehabilitation, the vast majority of trials aim at medical and surgical management—with specific attention paid to sequelae of SCI such as pain or hypertension—and not toward directed functional recovery of spinal cord tissue. In fact, aggressive medical management and physical rehabilitation are among the few approaches that have shown benefit following human trials, and can now be considered part of standard

care [113,123]. Early surgical decompression and functional electrostimulation have now been shown to deliver functional benefits [123], and will likely be added to treatment regimes throughout clinical practice. Historically, putative therapies have seen rises in popularity but exhibit little to no clinical success. Hypothermia has been applied with little standardization or scientific rigor, and trials have shown it is well tolerated, but incurs no neurological benefit [21,77]. This pattern holds true for many more putative treatments of SCI, including: CSF drainage, hormones, broad antiinflammatories and ion channel blockers [51,113]. 3.2. Improving therapeutic options Early attempts at a bioengineered approach toward SCI, such as tissue grafts and omentoplasty, were shown to produce no

Table 1 Registered human clinical trials for spinal cord injury by interventional category.a Interventional types

Total

Management Observational Medical/procedural Rehabilitation Surgical Prostheses and devices Imaging and diagnostics

84 51 43 17 15 12

Pharmacological Pain and spasticity Other sequelae Directed repair

53 35 21

Bioengineering Electrical stimulation FES (40), transcranial (7) Cell therapy BMSC (9), UCB (3), fetal (1), ES-OPC (1), OEC (1), AM (1)

222

109

47 16

Combination therapy

5

Total

386

Abbreviations: AM, activated macrophage; BMSC, bone marrow stromal cell; CNS, central nervous system; ES, embryonic stem cell; FES, functional electrical stimulation; OEC, olfactory ensheathing cell; UCB, umbilical cord blood. a As listed November 2011, with search of “spinal cord injury” and “spinal injury” and “SCI” on clinicaltrials.gov pre-screened for non-related hits and redundancies.

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appreciable improvements and never became indicated therapies [18,29]. Considering that the majority of drugs (if not all) that attempted have been abandoned, it begs the question as to why the aim of using directly applied pharmacologics (subdural gels) and more precise transplantable biologics (cells or biomaterials) have seen little-to-no study in human trial participants [71]. To counterbalance the disappointing results with pharmacological and tissue-graft treatments for SCI, there has been a surge of preclinical research on cell-based therapy over the past two decades [71,102,116]. These novel strategies aim at the direct repair and recovery of the cord, and not simply limiting primary injury with intravenous drugs. While the first generation of drugs proved to be ineffective, they informed the development of secondgeneration drugs, directly applied pharmacologics and biologics, as well as key considerations in how to design trials for SCI. 4. SCI trials: pharmacologics 4.1. Lessons learned from early trials Clinical trials involving pharmacologic therapeutics for SCI has been underway for more than three decades (see Tator [113] for thorough review) (Table 2). The majority of these have been systemically delivered drugs aimed at general neuroprotection, or reducing cell loss due to effects such as excitotoxicity. While more than a dozen such drugs have been shown to be well tolerated and safe in randomized controlled trials (RCTs), there is debate as to whether any have demonstrated enough functional benefit to be instated as part of standard care. Methylprednisolone, a corticosteroid administered as a sodium succinate (MPSS), was one of the first therapies to demonstrate efficacy in a large RCT. The National Acute Spinal Cord Injury Study (NASCIS) trials were large (up to 499 participants), multicenter, double-blind, prospective RCTs that demonstrated modest neurological improvements when MPSS was given within 8 h of injury (NASCIS I) for 24–48 h (NASCIS II, III) [6–8]. Alongside the landmark findings of the NASCIS trials were doubts as to the small effected subgroup, failure to reach primary endpoints, inconsistency between centers, infection rates, and blunt outcome measures employed [19,42]. Following 25 years of development in clinical testing, doubts surrounding the conclusive strength of the results from the NASCIS trials—along with fear of litigation from elevated infection-related adverse events—have caused the clinical use of MPSS to decline [57,91]. Concurrent to the NASCIS trials were the Sygen and Maryland trials of GM-1 (monosialotetrahexosylganglioside), an organic compound with multiple broad mechanisms for recovery following SCI. Similar to MPSS, the considerable (760 participant), doubleblind, second Sygen RCT did not achieve the substantial primary endpoint of 2 grades using the AIS/Frankel scores [42,43]. Despite the primary endpoint being met in the first GM-1 trial [44], or neurological benefit shown on secondary analysis for severe SCI in the second trial, no further studies involving GM-1 have been proposed. Thyrotropin releasing hormone (TRH) affects many actions along hypophysial axis, with potential attenuation of secondary injury mediators. A small placebo-controlled, double-blind RCT exhibited neurological benefit in participants with incomplete SCI, but was declared uninformative due to lack of outcome sensitivity and loss to follow-up, and has since been abandoned [90]. 4.2. Ion channel blockers Numerous ion channel blockers have been employed in the aim of inhibiting excitotoxic neuron death. 4-Aminopyridine (4AP; fampridine), a potassium channel blocker and avian pesticide, failed

to demonstrate beneficial effects in repeated, double-blind RCT in incomplete and chronic SCI [13,27]. However, 4AP is now entering Phase IV trials for Multiple Sclerosis [46] with FDA approval pending. HP184, a potassium/sodium channel blockade aimed at improved conductance of demyelinated axons, similarly failed to reach endpoints in a phase II double-blind multicenter trial [5]. Sanofi-Aventis sponsored the double-blind, phase II RCT with 262 chronic C4-T10 incomplete (AIS C/D) participants. This trial used AIS conversion rate at a single timepoint as the only outcome measure, and has been completed since 2005 without a published report. Gacyclidine, a d-aspartate NMDA receptor antagonist, demonstrated potential long-term benefit in a phase II prospective, multicenter, placebo-controlled RCT [76] but did not achieve primary outcome and was subsequently abandoned [33]. Nimodipine, a dihydropyridine calcium blocker, similarly failed to show efficacy in a prospective RCT [91]. Despite having demonstrated potential benefits in secondary analysis, these potential therapies have been largely abandoned. Clinical trial design, execution and the outcome measures chosen can be pivotal in the success of the trial.

4.3. Emergence of directed pharmacologics More recent pharmacological studies have incorporated a targeted modulation of the injured cord in carefully designed trials, with some therapeutics being applied directly to the spinal cord. Observing the shortcomings in earlier studies, the North American Clinical Trials Network (NACTN) re-tooled Riluzole, a benzothiazole anticonvulsant that acts as a sodium channel blocker that inhibits excitotoxicity similar to earlier blockades like HP184 or Nimodipine. Following completion of a thorough observational study with 36 participants, the 8-center NACTN is moving forward with a large phase IIb RCT using Riluzole with very explicit and multifactorial endpoint analyses. Minocycline is a long-acting broad-spectrum tetracycline antibiotic that has a proposed mechanism of immunomodulation through inhibition of microglia. Preclinical data of minocycline includes large reductions in oligodendrocyte apoptosis and macrophage/microglia density, tissue sparing with reduced axonal dieback, and functional motor recovery/benefit in preclinical rodent models [110,112,121]; however, concerns have been raised about independent replication [75,89]. Regardless, a phase III trial is underway in Calgary, Canada that combines minocycline and spinal perfusion pressure augmentation, with extensive outcome measures that include imaging, motor scores and pain. Cethrin (BA-210; Alseres, Inc.) is synthetic C3 transferase subunit of botulinum toxin bioengineered to efficiently cross the blood–spinal cord barrier and cell membranes, and holds some of the most promising clinical trial results to date. Cethrin effects RhoA inactivation and signal blockade of myelin-associated inhibition through the Nogo Receptor p75NTR complexes, resulting in neuroprotection and axonal regeneration with reduced lesion metrics and functional recovery in rodent models of acute SCI [80,98]. This approach is novel in that it targets the myelin-associated inhibition to endogenous regeneration, and it is applied directly to the spinal cord via subdural injection along the injury site. Initial safety trials showed good tolerance, and after questions about a phase II trial suspension [45], phase I/IIa trial results have been published that suggest neurological improvements with possible dose-response [35]. The direct application of this biologic provides an advantage over systemically administered antibodies that have been developed to reduce myelin-associated inhibition, such as anti-Nogo-A (Novartis) and anti-MAG (GSK) antibodies, which have little published preclinical or clinical data. The transition to targeted therapeutics is a rapidly trending approach to bioengineered SCI therapy.

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Table 2 Clinical trials for SCI involving bioengineered therapy. Therapy

Sponsor

Phase

Size

Population

Measures

Result

NCT ID#

Refs

Start

II III III III I/II

478 499 797 34 60

C5-T11, Ac C-T11, Ac C-T11, Ac C-T11, Ac C0-T11, Ac

NASCIS ASIA, FIM ASIA, Frankel ASIA, Benzel, FIM ASIA, FIM, SCIM

Neurological benefit

00004759

Trend to benefit Neurological benefit Recruiting

NR

[8] [6] [43] [42]

1990 1997 1991 2001 2010

I/II II II III

36 262 91 360

C4-T10, Ch C4-T10, Ch NR

ASIA, MAS, pain ASIA MAS NR

Safe Recruiting Reduced spasticity

00178724 NR NR 00041717

I/II II I I

48 200 46 52

C4-T12, Sub C5-C7, Ac C-T, Ch C5-T12, Ac

ASIA ASIA, FIM, SCIM Blood ASIA, blood

Trend to benefit Cancelled Recruiting Recruiting

Geron Corp. StemCells

I I/II

4 12

T3-T11, Su T2-T11

ISNCSCI Safety only

Brisbane, AU

I

6

T4-T10

Proneuron CSCIN CSCIN Gunzhou, CN

II I/II I/II

50 60 40 80

Toronto, CA Toronto, CA Baltimore, US

II III II/III

Boston, US

I

Pharmaceutical Immunomodulation MPSS NASCIS NASCIS GM-1 Maryland Sygen Calgary, CA Minocycline Channel inhibitor Riluzole NACTN HP184 Sanofi-Aventis Fampridine Acorda Acorda Environmental modification Alseres Cethrin Alseres Anti-MAG GSK Novartis Anti-NOGO Cell transplant NPC GRNOPC1 HuCNS-SC OEC MacKay-Sim MSC ProCord (AM) China (UCB) China (BMSC) FES Prostheses/FET MCRCT (UL) CURE-SCI (LL) Transcranial tDCS, Ch pain

00559494

n/a [13] n/a

2010 2004 2000 2002

00500812 00610337 00622609 00406016

[35]

2005

n/a n/a

2007 2006

Cancelled Recruiting

01217008 01321333

[61]

2010 2011

ASI, FIM

Ineffective

NR

[82]

2005

C5-T11, Sub C5-T11, Sub C5-T11, Ch T, Su

ASIA ASIA, SCIM, WISCI, MAS, VAS ASIA, Frankel, EMG

Cancelled Recruiting Recruiting Recruiting

00073853 01471613 01354483 01393977

[65]

2005 2011 2010 2011

40 84 80

C4-C7, Sub C4-C7, Sub Ch

FIM, SCIM GRASSP, FIM, SCIM CSF, MAS

Benefit, sustained Recruiting Recruiting

00221117 01292811 01217047

[92]

2005 2011 2010

60

Ch

EEG, VAS

Recruiting

01112774

2010

Ac, acute; AM, activated macrophage; ASIA, American Spinal Injury Association; BMSC, bone marrow stromal cell; Ch, chronic; CSCIN, China Spinal Cord Injury Network; FES, functional electrical stimulation; FET, FES therapy; FIM, functional independence measure; LL, lower limb; LP, lamina propria; MAS, Modified Ashworth Scale; MPSS, methylprednisolone sodium succinate; MSC, mesenchymal stem cell; n/a, completed but not published; NACTN, North American Clinical Trials Network; NASCIS, National Acute Spinal Cord Injury; NCT, National Clinical Trials database; NPC, neural precursor cell; NR, not registered; OB, fetal olfactory bulb; OEC, olfactory ensheathing cell; OPC, oligodendrocyte precursor cell; RCT, randomized controlled trial; SCI, spinal cord injury; SCIM, spinal cord independence measure; Sub, subacute; UCB, umbilical cord blood; UL, upper limb; VAS, pain visual analog scale; WISCI, walking in spinal cord injury.

5. Cell transplantation therapy 5.1. Preclinical success The use of cellular transplantation has been the focus of much preclinical research and includes myriad cell types and models of SCI (see Tetzlaff et al. [116] for systemic review). The rationale and advantage of this approach is the innate ability of cells to respond to the multifaceted pathophysiology of SCI. The proposed mechanism of action of any one cell type follows from its action during endogenous repair, including: (1) minimizing cell loss via immunomodulation by macrophages or umbilical cord blood cells (UCBs), (2) neuroprotection via trophic support by bone marrow stromal cells (BMSCs), (3) tissue modification via scaffolding/remyelination by myelin-producing Schwann cells (SCs) or olfactory ensheathing cells (OECs), and (4) regeneration via cell replacement/remyelination and plasticity by neural precursor cells (NPCs). Various cell transplantation paradigms have shown significant neurobehavioral benefit in rodent and large-animal models of SCI. Notable examples include the use of autologous OECs from nasal lamina propria [94,109], SCs from autologous sural nerve preparations [53,74], or re-administered autologous BMSCs [81,131]. The approach with the most consistent functional benefit, however, is the use of oligodendrocytes derived from adult or pluripotent NPCs. These NPCs have shown significant improvements to

lesion expansion, axonal regeneration, locomotion and sensory function [23,52,64]. ES-derived NPCs transplanted in perinatal hypomyelinated shiverer mouse were capable of total repopulation of CNS myelin, correcting the lethal shiverer phenotype [124]. More detailed discussion on specific stem cell mechanisms in SCI can be found in Miller (2012, in this issue) and elsewhere [96,99,101,126]. 5.2. Non-neural stem cells: macrophage, BMSC and UCB The first RCT of cell therapy in SCI was the ProCord trial evaluating activated macrophages [66]. Sponsored by Proneuron Biotech, the trial involved the isolation of patient-specific macrophages that were manipulated ex vivo, and then reintroduced into the injured spinal cord. A phase II trial was initiated with sites in the United States and Israel, enrolling participants with acute, complete, low-cervical/thoracic SCI. While this trial set new precedence, the preclinical data was sparse (reviewed elsewhere [33,97]) and has since been shown to be ineffective in a large animal (dog) model of SCI [4]. Amid difficulties stemming from inclusion criteria and inconsistency in surgical and medical management of potential participants, the ProCord phase II RCT was suspended in 2003 citing financial constraints [61]. The ProCord trials demonstrate the difficulties executing SCI trials, specifically the large funnel effect (50 participants from 1816 pre-screened patients), ASIA conversion as a primary outcome, and paucity of preclinical data.

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Several evaluations of BMSCs in SCI have been conducted, including published case studies in Korea [87], Japan [100], and Argentina [85]. While not capable of drawing conclusions about the therapy, these studies evaluate ASIA conversion and electrophysiological analyses to determine safety of the transplant. Registered phase I trials of BMSC transplantation have also been reported, with demonstration of safety in the Czech Republic [111] and Brazil [12]. These trials include at least one report of appreciable improvement in a neurologically stable, chronic patient [111], suggesting the therapeutic window may go beyond the 4-week mark. Larger phase I/II RCTs have also been reported in Korea measuring ASIA conversion [130], and in Russia where ASIA, Ashworth spasticity scale and quality-of-life surveys were conducted [17] (both unregistered). Researchers in China have begun conducting RCTs, signaling a change from reportedly performing thousands of unsystematic cellular transplants. Currently, there are two registered trials of BMSCs in China, with 20 and 80 patients in a phase I/II and III study, respectively. There are also three registered RCTs evaluating UCBs, with a combined prospective study size of 100 participants. These account for every registered trial involving umbilical cord-derived cells in SCI, with nearly one-third of all registered trials now coming from China. The results of these trials are highly anticipated, as it may signal China’s emergence as a key player in regenerative medicines for SCI. 5.3. Peripheral myelinating cells: OEC Schwann cells and OECs are not stem cells per se, but are capable of rapid amplification, migration and myelin production. While Schwann cells (SCs) have been well studied in preclinical models [116], the authors are not aware of any large case studies or RCTs employing SC transplantation in humans. Several case studies and small RCTs have been conducted with OECs isolated from patient’s own nasal lamina propria (LP) in Poland, Portugal [79], and Australia [37], and from aborted fetal olfactory bulbs (OB) in China [54]. The MacKay-Sim trials conducted in Australia present an extensive 3-year follow-up of six patients after autologous LP-OEC transplantation. This study included a control group, and benefited from a myriad of outcome measures including radiological (MRI), motor function (ASIA/FIM), sensory function (SSEP), spasticity and pain [83]. No radiological changes or neuropathic pain were observed, however, neither were neurological improvements. The largest array of patients treated to date has been in China, where more than 400 patients have received OB-OEC transplants [28]. The published results of these cases with OB-OEC transplants indicate improvements were seen in neurological function [54]; however, independent case study follow-up conducted in the United States cannot confirm this to be true [28]. Nevertheless, an independent surgeon scientist has confirmed rapid and significant improvements in a neurologically stable patient following OB-OEC transplantation [47], and registered trials with more appropriate/thorough clinical assessment and follow-up have begun in Chinese centers. 5.4. Pluripotent cells: Geron trial The paradigm that has garnered the most convincing groundwork from preclinical data is the use of pluripotent cell-derived NPCs or oligodendrocyte progenitor cells (OPCs). This paradigm was tested in what is now the most well known cell-based SCI clinical trial: the Geron-sponsored trial of GRNOPC1 cells. Geron Corp. (Menlo Park, CA) announced FDA approval of their near 22,000 page IND in January 2009, that proposed treating 10 patients in multi-center trial with a single-dose of 2 × 106 hESC-derived OPCs at 7–14 days post-injury. With inclusion criteria of only complete (AIS A) thoracic participants, and the only adjuvant being low-dose

tacrolimus for 60 days, adverse events were not expected [3,20]. The neurological test employed in the trial, the international standards for neurological classification of spinal cord injury (ISNCSCI), exhibits high sensitivity, internal reliability and repeatability for complete injury [84]. However, all preclinical data—including the published studies by Keirstead et al. [65]—suggested that the cell therapy has highest therapeutic potential when used in contusive, incomplete injury. The Geron safety and feasibility study was ultimately cancelled in November 2011 with only 4 participants enrolled. The reason cited for this cancellation was financial constraints, with losses known to be in the order of $110 million in 2010 fiscal year, resulting in Geron cutting 38% of its workforce and jeopardizing its government partnerships [62]. It is suspected that this plummet would not have continued should benefit have been reported, and Geron’s chief medical officer Stephen Kelsey has confirmed that the four patients who received GRNOPC1 did not show any signs of benefit [62]. The inclusion criteria for enrolled participants of this first-in-human study has been the topic of much debate, with bioethicist commentators claiming the trialists exhibited ethical hubris and committed a tragedy of translation [107], and scientists declaring that safety studies ought to have enrolled incomplete or chronic SCI [11]. To those with first-hand familiarity with the great aptitude and drive of persons that have suffered spinal injuries, however, these objections appear to be myopic. Moreover, the inclusion criteria was designed to optimize for sensitivity in identifying any OPC-related improvement (i.e., conversion of AIS A or subsequent ISNCSCI scores) which was carefully chosen by the trialists [125]. Other firms such as Advanced Cell Technology, BioTime or Pfizer could purchase or license the GRNOPC1 technology, however, it is unlikely that the original trial will be revived.

5.5. Adapting successful trials The field of pluripotent cell-derived therapy in humans has been initiated and is poised to advance, however, translation of cell transplantation is still at very early stages. Of 16 registered clinical trials that evaluating cell transplantation and SCI, 14 (88%) are phase I or I/II with a median enrollment size of only 12 participants (Table 1). Cell-based trials can proceed using lessons learned from previous trials, with explicit attention to the closure of first spinal cell transplantation trials (e.g. ProNeuron, Geron). Successful adaptation of cell therapy will likely include: multiple sites to increase enrollment, participants with incomplete and possibly cervical SCI, sponsorship by government and/or non-publicly traded companies, and compound sensorimotor outcome measures (such as ISNCSCI or SCIM) in the primary endpoint. The next wave of cell therapy have been initiated by StemCells Inc. and NeuralStem Inc. using human CNS-derived NPCs [82], with phase I trials scheduled to commence in 2011 and 2012, respectively. Conversely, cell transplantation is already big business for international commercial clinics offering so-called stem cell therapy. These clinics, the majority of which provide intrathecal/intravascular-administered BMSCs or UCBs, have been in operation for years and recruit British and North American customers [73]. Seemingly ubiquitous, these clinics operate in countries throughout the world including China, Russia, Mexico, Ukraine, United States, India, Thailand, etc. (see [73] for a listing). In May of 2011, the XCell-Centre operating in German within regulatory loopholes was shut down following the death of an 18-year old boy who received an injection of cells to the brain (unpublished independent news reports), demonstrating the potential risk to the public. While commoditization of stem cells is not objectionable a priori on ethical or pragmatic grounds [16], numerous unregulated

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commercial clinics contribute to mistrust of conscientious medical research [15].

6. Bioengineered strategies 6.1. Electrical stimulation for neuroplastic repair In contrast to the very preclinical research-driven field of cell-based therapy, the application of electrical stimulation and functional modulation is driven almost entirely from clinically research. Of the 386 registered clinical trials, 40 (10%) involve the use of functional electrical stimulation (FES) for neurorehabilitation, and 7 (2%) involve transcranial direct current stimulation (tDCS) and magnetic stimulation (tMS) for pain (Table 1). The application of the electrical or magnetic field stimulus is realized with surface or implanted electrodes, and has advanced greatly in the past decade [92,122]. Target functions hand and arm flexion, ambulation, diaphragm contraction, bladder and bowel voiding, or direct cortical interfacing. These trials typically follow a case study paradigm, with the average participant size of 34 skewed toward small (n = 5) pilot studies. The biomedical engineering approach to these RCTs builds on the robust success of physical rehabilitation, allowing activation to entrain motor functions beyond the capacity of atrophied tissue. Surface FES applied in conjunction with prostheses, or neuroprostheses, have been employed to improve lower limb muscle volume, strength, standing and tissue metabolism during assisted exercise [59,60,106]. When applied to the torso, FES neuroprostheses also improve forceful pulling, kyphosis, standing, and functional independence [2,117]. Application of FES to the hand and upper limb has achieved improvements in neurological outcome such as hand grasping, strength and SCIM subscores in subacute incomplete tetraplegia [88,93]. Remarkably, these neurological improvements are retained even after the device is removed and FES is discontinued. With the rapid technological advances of the last decade, hand neuroprostheses have been designed for ultimate ease-ofuse linking lost motor units to preserved tongue and neck flexion with Bluetooth and myoelectric connection [50]. Remarkably, a recent case study showed that extensive training combined with an epidural array in the lumbar spine that integrates supraspinal and sensory control could return of weight-bearing standing, volitional motor function, and some rhythmic stepping in a patient with complete paraplegia [48]. Additionally, non-invasive transcranial activation of the cortex through tDCS and tMS are being applied to alleviate neuropathic pain and induce plasticity to improve behavioral outcomes [38,40]. These approaches are changing the face of neurorehabilitation, allowing for exciting advances in the treatment of SCI and insult to the CNS. Additional discussion of neural repair following FES can be found in Goldberg and Palmer (in this issue) and elsewhere [39,92].

6.2. Environmental modification and biomaterials Removing inhibition and glial scarring is a key target to enable further neuroplastic recovery and neurorehabilitation. This approach has been studied in preclinical models, but has yet to be translated into human trials. One major avenues of promoting neuroplasticity is degradation of the glial scar subunits through enzymes such as chondroitinase ABC (ChABC). Following ChABCmediated degradation of gliotic proteoglycans, neurite outgrowth, collateral sprouting, synaptic plasticity and axonal regeneration are upregulated [9,10]. This can induce marked recovery of sensorimotor functions, even after atrophy and degeneration in chronic injury [14,49,64]. Encouragingly, the effects of ChABC significantly

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improved with the rehabilitation in rats, which can be modulated by the neurorehabilitation performed [41]. It is well known that peripheral nerve grafts can provide a regenerative scaffold for central nerve axons [24]. Scaffolds made of porous polymer biomaterials can be used in the place of PNS grafts, and when seeded with NPCs can provide marked functional recovery through improved axonal regeneration [115]. However, implanting a solid object into the injured cord is not clinically translatable. To overcome this, hydrogels and self-assembling peptides have been developed to provide injectable scaffolds [104,120]. These biomaterials can be modified to deliver drugs or stem cells, and have been shown to provide functional recovery in rodent models of SCI [119,120]. Regardless of the structure and delivery of these environmental modifiers and injectable scaffolds, the authors believe that an approach combining biomaterials, cell-based transplants and neurorehabilitation will provide the highest likelihood of success in treating SCI. 7. Considerations for future clinical trials A growing perception by Big Pharma of minimal financial returns for SCI therapy is leading its appearance as an orphan disease in the private sector. Clinical trials must be thoroughly designed and expertly executed if they are to be carried forward by government funding or co-sponsorship, such as with Geron’s support by California through CIRM [62]. The incidence and natural history of SCI also pose specific challenges, with the majority of patients suffering from chronic cervical SCI. An incredibly varied population presents a significant funnel effect, which is magnified by the fact that patients have 10 significant adverse events on average. This contributes a significant barrier to meaningful safety studies, and leads trialists to create prohibitive exclusion criteria. To counteract these difficulties, trials should employ compound measures in the primary endpoint, providing inclusion of motor subscores, upper limb subscores, hand function [63], spasticity, pain, SCIM and subscores during analysis. Careful attention must also be paid to the enrolled population. The balance of sensitivity, specificity, and therapeutic threshold is struck between the chronic, compete, thoracic patients and the subacute, incomplete, cervical populations. Finally, multicenter clinical trials networks such as NACTN are also required to best realize clinical research. Partnership between the private sector, government and NGOs is pivotal to drive clinical research. 8. Closing remarks Current advances in regenerative medicines have lead to great demand for therapies of neurological and neurodegenerative disease—specifically, those that could be afforded by cell-based and bioengineered solutions. The expectations placed on clinical trials of bioengineered therapies for SCI must be measured and well informed by translationally focused preclinical data. This has been evidenced by the past decade of human clinical trials involving stem cell transplantation, including suspension of key clinical trials. Smaller clinical trials of FES and other bioengineering approaches have shown promise, however, and the next phase of large-scale clinical trials are in progress. References [1] A. Ackery, C. Tator, A. Krassioukov, A global perspective on spinal cord injury epidemiology, J. Neurotrauma 21 (2004) 1355–1370. [2] S. Agarwal, R.J. Triolo, R. Kobetic, M. Miller, C. Bieri, S. Kukke, L. Rohde, J.A. Davis Jr., Long-term user perceptions of an implanted neuroprosthesis for exercise, standing, and transfers after spinal cord injury, J. Rehabil. Res. Dev. 40 (2003) 241–252.

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