Intraspinal Infusion of Bone Marrow Mononuclear Cells to Treat Amyothrophyc Lateral Sclerosis, Results of a Controlled Phase I-II Study
Authors: Blanquer Miguel , Iniesta Francisca , Perez-Espejo Miguel Angel , Meca Jose , Espuch Joaquín Gómez , Villaverde Ramón , Izura Virginia , Ruiz Francisco Jose , Bleda Patricia , Antunez Carmen , Carles Rafael , Hernandez Joaquin , Santos Jose Maria , Majado Maria Juliana , Moraleda Jose Maria 
Published: April 2020

Abstract
Introduction: Patients with Amyothrophyc Lateral Sclerosis (ALS) typically endure a progressive paralysis due to the continued loss of motoneurons that leads them to death in less than 5 years. No treatment has changed its natural history. Intraspinal injections of bone marrow mononuclear cells (MNC) have been able to ameliorate the course of ALS in murine models, acting as pumps of trophic factors that keep the motoneurons functional. We have designed a phase I/II clinical trial to check the feasibility of this approach in humans.
Material and Methods: 10 patients were required for this study. Inclusion criteria required a medullar onset of the disease, a forced vital capacity (FVC) &gt;50% and under 90% desaturation time inferior to 2% of the sleeping time. Sixty mL of bone marrow were harvested under sedation. A ficoll procedure was performed in order to obtain the MNC, which were resuspended in 2 mL of saline. After laminectomy, the MNC were infused through a spinal needle in 2 injections 10 and 6 mm deep in the posterior tract of T3–T4 under electrophysiological surveillance. This level was chosen aiming the preservation of the lower intercostals function as a mean to stop the deterioration of the FVC, and thus prolong this patient’s survival. Patients are followed for 6 months before the infusion, to establish the individual evolution of the disease, and every three months for 1 year after the procedure.
Results: 26 of 116 clinical histories submitted for revision to enter the trial initially met the inclusion criteria. Out of 26, 15 patients had to be excluded because they didn’t meet the inclusion criteria either in the first or subsequent visits prior to the procedure. Seven patients, 3 males and 4 females (median age 46 years, range 32 – 61) have been infused so far. All patients had received multiple prior medical treatments. Median time from diagnosis to cellular infusion was 20 months (range 15 – 47). We infused a total of 402 ×106 (240–602.8) MNC, including 3.16 ×106 (0.96–10.25) CD34+ cells. After ≥6 months of follow-up, assessment of the FVC’s evolution and the score points of the international ALS-FRS, Norris and MRC scales, revealed that of two rapidly evolving patients, one achieved stabilization of the progression and one was unaffected by the intervention. Five patients whose disease evolved more slowly also achieved stabilization of the functional scales or maintained basal FVC values (Fig. 1). Serial magnetic resonance image studies did not show any spinal cord damage. There were two severe adverse reactions (AE): 1 syncope secondary to constipation, and 1 admission due to a high tract respiratory infection with transient respiratory insufficiency in the patient in which the transplant was ineffective. Other AEs of WHO grade 1 or 2 and less than 2 months of duration were: constipation (7), intercostal pain (3), CSF hypotension (2) and lower limbs paresthesias (5, 1 of them persistent). After 6 months of follow-up, all patients had asymptomatic abolition of the somato-sensorial potentials of the posterior tract.
Conclusions: The procedure was safe and feasible. No major complications or significant morbility was observed. Stabilization of the disease was achieved in 6 of the first 7 patients included in the protocol. The only unresponsive patient had developed bulbar involvement at the time of the infusion, an already known adverse prognostic factor for response to this type of cellular therapy.
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