title: Neurotrophic bone marrow cellular nests prevent spinal motoneuron degeneration in amyotrophic lateral sclerosis patients: a pilot safety study.
abstract: The objective of this article is to assess the safety of intraspinal infusion of autologous bone marrow mononuclear cells (BMNCs) and, ultimately, to look for histopathological signs of cellular neurotrophism in amyotrophic lateral sclerosis (ALS) patients. We conducted an open single arm phase I trial. After 6 months observation, autologous BMNCs were infused into the posterior spinal cord funiculus. Safety was the primary endpoint and was defined as the absence of serious transplant-related adverse events. In addition, forced vital capacity (FVC), ALS-functional rating scale (ALS-FRS), Medical Research Council scale for assessment of muscle power (MRC), and Norris scales were assessed 6 and 3 months prior to the transplant and quarterly afterward for 1 year. Pathological studies were performed in case of death. Eleven patients were included. We did not observe any severe transplant-related adverse event, but there were 43 nonsevere events. Twenty-two (51%) resolved in ≤2 weeks and only four were still present at the end of follow-up. All were common terminology criteria for adverse events grade ≤2. No acceleration in the rate of decline of FVC, ALS-FRS, Norris, or MRC scales was observed. Four patients died on days 359, 378, 808, and 1,058 post-transplant for reasons unrelated to the procedure. Spinal cord pathological analysis showed a greater number of motoneurons in the treated segments compared with the untreated segments (4.2 ± 0.8 motoneurons per section [mns per sect] and 0.9 ± 0.3 mns per sect, respectively). In the treated segments, motoneurons were surrounded by CD90+ cells and did not show degenerative ubiquitin deposits. This clinical trial confirms not only the safety of intraspinal infusion of autologous BMNC in ALS patients but also provides evidence strongly suggesting their neurotrophic activity.
authors.affiliation: Hematopoietic Progenitors Transplant and Cell Therapy Unit, Hospital Virgen de la Arrixaca, Universidad de Murcia, Murcia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanquer
authors.forename: Jose M
authors.initials: JM
authors.lastname: Moraleda
authors.forename: Francisca
authors.initials: F
authors.lastname: Iniesta
authors.forename: Joaquín
authors.initials: J
authors.lastname: Gómez-Espuch
authors.forename: José
authors.initials: J
authors.lastname: Meca-Lallana
authors.forename: Ramón
authors.initials: R
authors.lastname: Villaverde
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Pérez-Espejo
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: Ruíz-López
authors.forename: José María
authors.initials: JM
authors.lastname: García Santos
authors.forename: Patricia
authors.initials: P
authors.lastname: Bleda
authors.forename: Virginia
authors.initials: V
authors.lastname: Izura
authors.forename: María
authors.initials: M
authors.lastname: Sáez
authors.forename: Pedro
authors.initials: P
authors.lastname: De Mingo
authors.forename: Laura
authors.initials: L
authors.lastname: Vivancos
authors.forename: Rafael
authors.initials: R
authors.lastname: Carles
authors.forename: Judith
authors.initials: J
authors.lastname: Jiménez
authors.forename: Joaquín
authors.initials: J
authors.lastname: Hernández
authors.forename: Julia
authors.initials: J
authors.lastname: Guardiola
authors.forename: Silvia Torres
authors.initials: ST
authors.lastname: Del Rio
authors.forename: Carmen
authors.initials: C
authors.lastname: Antúnez
authors.forename: Pedro
authors.initials: P
authors.lastname: De la Rosa
authors.forename: Maria Juliana
authors.initials: MJ
authors.lastname: Majado
authors.forename: Andrés
authors.initials: A
authors.lastname: Sánchez-Salinas
authors.forename: Javier
authors.initials: J
authors.lastname: López
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: Martínez-Lage
authors.forename: Salvador
authors.initials: S
authors.lastname: Martínez
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology* / Q000601:surgery*; D001854:Bone Marrow Cells / Q000473:pathology*; D016026:Bone Marrow Transplantation / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology*; D010865:Pilot Projects; D013116:Spinal Cord / Q000473:pathology* / Q000601:surgery