A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury.

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or cervical (C4-T1) SCI were sequentially recruited for this dose-ranging (0.3 mg to 9 mg Cethrin), multi-center study of 48 patients with complete American Spinal Injury Association assessment (ASIA) A. Vital signs; clinical laboratory tests; computed tomography (CT) scans of the spine, head, and abdomen; magnetic resonance imaging (MRI) of the spine, and ASIA assessment were performed in the pre-study period and in follow-up periods out to 1 year after treatment. The treatment-emergent adverse events that were reported were typical for a population of acute SCI patients, and no serious adverse events were attributed to the drug. The pharmacokinetic analysis showed low levels of systemic exposure to the drug, and there was high inter-patient variability. Changes in ASIA motor scores from baseline were low across all dose groups in thoracic patients (1.8±5.1) and larger in cervical patients (18.6±19.3). The largest change in motor score was observed in the cervical patients treated with 3 mg of Cethrin in whom a 27.3±13.3 point improvement in ASIA motor score at 12 months was observed. Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in SCI patients are planned, to establish evidence of efficacy.

Spinal cord injury and neural repair: focus on neuroregenerative approaches for spinal cord injury.

BACKGROUND: This review discusses the urgent need for improved therapeutic approaches aimed at restoring function following traumatic spinal cord injury (SCI). The focus of this paper is neuroregenerative approaches for SCI, with a highlighted comparison of recent advances in the field and comparisons to that made by Cethrin (Alseres Pharmaceuticals, Inc.), the leading nerve repair product. OBJECTIVE: This review first provides the reader with an understanding of SCI. The market for promising therapeutics that can either intervene in secondary etiological mechanisms or ameliorate symptoms associated with SCI are then discussed. The reader will also learn about Cethrin and its current status in clinical evaluation. METHODS: Review of the preclinical literature and clinical SCI trials relevant to the discovery and current development of Cethrin. RESULTS/CONCLUSION: In a recently concluded Phase I/IIa clinical trial involving 37 patients with either cervical or thoracic SCIs, the evidence for Cethrin indicates that topical administration of either 0.3, 1, 3 or 6 mg of the recombinant rho inhibitor following surgical decompression is safe. Alseres has announced that planning is underway for a Phase IIB trial of Cethrin to include a placebo arm to assess better the drugs' clinical efficacy.

Gene expression profiling in anti-CD11d mAb-treated spinal cord-injured rats.

Acute administration of a mononclonal antibody (mAb) raised against the CD11d subunit of the leukocyte CD11d/CD18 integrin after spinal cord injury (SCI) in the rat greatly improves neurological outcomes. We have profiled gene expression in anti-CD11d and isotyped-matched control mAb-treated rats after SCI. Microarray analysis demonstrated reduced expression of pro-inflammatory cytokines and increased expression of inflammatory mediators that promote wound healing and the expression of scar proteins predicted to improve nerve growth. These changes in gene expression may reflect changes in the types of macrophages that populate the lesions in anti-CD11d mAb-treated rats.

Spinal cord injury: the promise of translational research.

Spinal cord injury (SCI) is a condition with devastating consequences for the patient, family, and society. Although effective treatments for SCI remain limited, there have been many advances in recent years, which have promise for the future from a clinical translational perspective. This issue of Neurosurgical Focus explores some of the current basic science, preclinical, and clinical research directed towards this goal. Clinical investigations are also discussed with regard to the treatment and management of different types of SCI and of SCI in different populations. The issue concludes with a review of the current, ongoing, and planned clinical trials, providing a glimpse of the promising new therapies being developed for the treatment of SCI.

Transcriptional regulation of scar gene expression in primary astrocytes.

The failure of the adult injured spinal cord to support axonal regeneration is in part attributed to the glial scar. Reactive astrocytes constitute a major cellular component of the glial scar and are heterogeneous with respect to the extracellular matrix proteins that they secrete. Astrocytes may produce antiregenerative molecules such as chondroitin sulphate proteoglycans (CSPGs) or proregenerative molecules such as laminin and fibronectin. While many different CSPGs are expressed after spinal cord injury (SCI) they all rely on the same enzymes, xylosyltransferase-I and -II (XT-I, XT-II) and chondroitin 4-sulfotransferase (C4ST) to add the repulsive chondroitin sulfate side chains to their core proteins. We show that XT-I, XT-II, and C4ST are part of a CSPG biosynthetic gene (CBG) battery. Using primary astrocyte cultures and quantitative PCR we demonstrate that TGFbeta2, PDGF, and IL-6 induce the expression of CBGs, laminin and fibronectin by several-fold. We further show that over-expression of the transcription factor SOX9 also strongly induces the expression of CBGs but does not increase the expression of laminin or fibronectin. Correspondingly, SOX9 knock-down in primary astrocytes causes a decrease in CBG and an increase in laminin and fibronectin mRNA levels. Finally, we show that the in vivo expression profiles of TGFbeta2, PDGF, IL-6, and SOX9 are consistent with their potential roles in differentially regulating CBGs, laminin and fibronectin gene expression in the injured spinal cord. This work suggests that SOX9 levels may be pivotal in determining the balance of pro- and anti-regenerative extracellular matrix molecules produced by astrocytes.