Intramuscular Injection of Bone Marrow Stem Cells in Amyotrophic Lateral Sclerosis Patients: A Randomized Clinical Trial.

BACKGROUND: Preclinical studies suggest that stem cells may be a valuable therapeutic tool in amyotrophic lateral sclerosis (ALS). As it has been demonstrated that there are molecular changes at the end-plate during the early stages of motorneuron degeneration in animal models, we hypothesize that the local effect of this stem cell delivery method could slow the progressive loss of motor units (MUs) in ALS patients. METHODS: We designed a Phase I/II clinical trial to study the safety of intramuscularly implanting autologous bone marrow mononuclear cells (BMMCs), including stem cells, in ALS patients and their possible effects on the MU of the tibialis anterior (TA) muscle. Twenty-two patients participated in a randomized, double-blind, placebo-controlled trial that consisted of a baseline visit followed by one intramuscular injection of BMNCs, follow-up visits at 30, 90, 180, and 360 days, and an additional year of clinical follow-up. In each patient, one TA muscle was injected with a single dose of BMMCs while the contralateral muscle was given a placebo; the sides were selected randomly. All visits included a complete EMG study of both TA muscles. RESULTS: Our results show that (1) the intramuscular injection of BMMCs is a safe procedure; (2) ALS patients show heterogeneities in the degree of TA injury; (3) a comparison of placebo-injected muscles with BMMC-injected muscles showed significant differences in only one parameter, the D50 index used to quantify the Compound Muscle Action Potential (CMAP) scan curve. This parameter was higher in the BMMC-injected TA muscle at both 90 days (placebo side: 29.55 ± 2.89, n = 20; experimental side: 39.25 ± 3.21, n = 20; p < 0.01) and 180 days (placebo side: 29.35 ± 3.29, n = 17; experimental side: 41.24 ± 3.34, n = 17; p < 0.01). CONCLUSION: This procedure had no effect on the TA muscle MU properties, with the exception of the D50 index. Finding differences in just this index supports the fact that it may be much more sensitive than other electrophysiological parameters when studying treatment effects. Given the low number of patients and their heterogeneity, these results justify exploring the efficacy of this procedure in further patients and other muscles, through Phase II trials. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (identifier NCT02286011); EudraCT number 2011-004801-25.

Response to Novel Drugs before and after Allogeneic Stem Cell Transplantation in Patients with Relapsed Multiple Myeloma.

Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P < .001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P < .001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment.

Spinal cord infusion of stem cells in amyotrophic lateral sclerosis: Magnetic resonance spectroscopy shows metabolite improvement in the precentral gyrus.

BACKGROUND AIMS: We aimed to investigate whether magnetic resonance spectroscopy (MRS) metabolite ratios change in the precentral gyrus of patients with amyotrophic lateral sclerosis (ALS) after spinal cord surgical injection of bone marrow mononuclear cells, as well as their relationship with disability and survival. METHODS: Stem cells were surgically injected in the spinal cord of 11 spinal-onset amyotrophic lateral sclerosis patients (group 1); 21 matched patients were the control group (group 2), comprising ALS patients with an intrathecal saline infusion. Single-voxel 1.5T MRS was performed in both precentral gyri just after inclusion/baseline (before surgery in group 1) and a year later (7 patients in group 1 and 11 in group 2). The spectroscopy data, time of survival and clinical parameters (ALS Functional Rating Scale, forced vital capacity [FVC], Medical Research Council Score) were longitudinally assessed and correlated in both groups. RESULTS: Only in group 1was there a significant N-acetyl-aspartate/creatine (NAA/Cr) increase with time in the dominant side (P = 0.024). NAA/Cr also correlated with years of survival in the nondominant side (r = 0.808, P = 0.026). Except for FVC, all group 1 clinical parameters at 12 months correlated with baseline NAA/Cr on both sides (P <0.05); this was not the case in group 2. DISCUSSION: In view of these results, we speculate on a distant beneficial effect of bone marrow stem cells injected at the spinal cord over the upper motor neuron at the precentral gyri in the brain. Spinal cord injection of stem cells shows metabolic improvement in the brain that might be related to longer survival and less disability.

Breathing pattern in a phase I clinical trial of intraspinal injection of autologous bone marrow mononuclear cells in patients with amyotrophic lateral sclerosis.

The safety of autologous bone marrow mononuclear cells (ABMNC) intraspinal infusion in amyotrophic lateral sclerosis (ALS) patients was evaluated considering breathing and sleep patterns. Patients between 20 and 65 years old were eligible if they had definite ALS, spinal onset, a disease duration between 6 and 36 months, FVC>50%, and a below 90% oxygen saturation (T90) <2% of sleep time. The transplant was performed 6 months after enrollment. ABMNC were infused at thoracic 3-4 level. Eleven patients were included. The REM sleep decreased slightly one year after the cell transplant but not significantly. There were no differences in apnea-hipopnea index, mean oxygen saturation and nadir desaturation evolution. An increase of T90 was observed 180 and 360 days after injection (2.95±1.51% and 4.30±4.10% respectively), although it was not statistically significant. The central drive determined by occlusion pressure (P01) and inspiratory flow showed non-significant differences after one year. Intramedullary injection of ABMNC did not worsen the cortico medullar diaphragmatic pathways.

Acute and chronic MRI changes in the spine and spinal cord after surgical stem cell grafting in patients with definite amyotrophic lateral sclerosis: post-infusion injuries are unrelated with clinical impairment.

OBJECTIVE: To report MRI spinal changes after surgical infusion of bone marrow stem cells (BMSc) in ALS patients and assess their correlation with clinical events and functional performance. METHODS: BMSc were surgically injected in the thoracic spinal cord of 11 ALS patients (6/5 male/female; median age 46years). We performed first-week and third, sixth, ninth and twelfth post-surgical months spinal MRIs. The spinal changes in the postsurgical week and follow-up MRIs, as well as clinical events, functional scales and respiratory and electromyography data, were longitudinally monitored. Correlations between the imaging and clinical data were evaluated with the Spearman's test. RESULTS: Transient extradural fluid collections (100%), transient spinal cord T2 hyperintensity (81.8%), and chronic spinal cord deformities (63.6%) were the dominating MRI changes. Spinal cord hemorrhages (27.3%) and cystic myelomalacia (1/11 patients) were important although unusual findings. During the follow-up, minor adverse events of mild to moderate intensity eventually improved. Initial and follow-up imaging scores showed a strongly positive correlation (r 0.879, P<0.001). The initial and delayed clinical scores did not correlate. There was no significant correlation between any of the imaging scores and clinical data. CONCLUSIONS: Infusion of BMSc produces a variety of spinal changes apparently unrelated with clinical events and disease worsening.

Mesenchymal dental stem cells in regenerative dentistry

In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration (AU)

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Mesenchymal dental stem cells in regenerative dentistry.

In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration.

Neurotrophic bone marrow cellular nests prevent spinal motoneuron degeneration in amyotrophic lateral sclerosis patients: a pilot safety study.

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.

A surgical technique of spinal cord cell transplantation in amyotrophic lateral sclerosis.

We report an original method for implanting bone marrow stem cells within the spinal cord parenchyma. This method was used for the experimental treatment of patients diagnosed with amyotrophic lateral sclerosis. The methodology is reproducible and devoid of major complications even in patients showing significant spinal atrophy. Therefore, this report describes a surgical procedure that could be used in other experimental treatments involving the intraspinal delivery of stem cells.