First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury
| Autor: | Martin E. Schwab, Armin Curt, Klaus Kucher, Norbert Weidner, Steven Casha, Anis Mir, R Rupp, Rainer Abel, Renate Meindl, Donald Johns, Baltazar Gomez-Mancilla, Hagen Christopher Baron, Roland Thietje, Christian Pfister, Andreas Badke, Doris Maier |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Nogo Proteins medicine.medical_specialty Neurology Adolescent Neurite Central nervous system Pharmacology Quadriplegia Inhibitory postsynaptic potential Young Adult 03 medical and health sciences 0302 clinical medicine Neurites medicine Humans Tetraplegia Spinal cord injury Injections Spinal Spinal Cord Injuries Paraplegia Dose-Response Relationship Drug business.industry Recovery of Function General Medicine Middle Aged medicine.disease Nerve Regeneration Treatment Outcome 030104 developmental biology medicine.anatomical_structure Immunoglobulin G Feasibility Studies Female business 030217 neurology & neurosurgery |
| Zdroj: | Neurorehabilitation and Neural Repair. 32:578-589 |
| ISSN: | 1552-6844 1545-9683 |
| DOI: | 10.1177/1545968318776371 |
| Popis: | Background. Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery. Objective. This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia. Methods. Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks). Results. ATI355 was well tolerated up to 1-year follow-up. All patients experienced ≥1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia. Conclusions. ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI. |
| Databáze: | OpenAIRE |
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