A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

Introduction/aims: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression.

Methods: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization.

NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results.

Objective: To determine the safety and efficacy of mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells (NurOwn®, autologous bone marrow-derived MSCs, induced to secrete NTFs) delivered by combined intrathecal and intramuscular administration to participants with amyotrophic lateral sclerosis (ALS) in a phase 2 randomized controlled trial.

Methods: The study enrolled 48 participants randomized 3:1 (treatment: placebo). After a 3-month pretransplant period, participants received 1 dose of MSC-NTF cells (n = 36) or placebo (n = 12) and were followed for 6 months.

Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis: Results of Phase 1/2 and 2a Clinical Trials.

Importance: Preclinical studies have shown that neurotrophic growth factors (NTFs) extend the survival of motor neurons in amyotrophic lateral sclerosis (ALS) and that the combined delivery of these neurotrophic factors has a strong synergistic effect. We have developed a culture-based method for inducing mesenchymal stem cells (MSCs) to secrete neurotrophic factors. These MSC-NTF cells have been shown to be protective in several animal models of neurodegenerative diseases.

Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease.

Stem cell-based therapy is a promising treatment for neurodegenerative diseases. In our laboratory, a novel protocol has been developed to induce bone marrow-derived mesenchymal stem cells (MSC) into neurotrophic factors- secreting cells (NTF-SC), thus combining stem cell-based therapy with the NTF-based neuroprotection. These cells produce and secrete factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor.

Induction of adult human bone marrow mesenchymal stromal cells into functional astrocyte-like cells: potential for restorative treatment in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder with its motor phenomena due mostly to loss of dopamine-producing neurons in the substantia nigra. Pharmacological treatments aimed to increase the deficient dopaminergic neurotransmission are effective in ameliorating the cardinal symptoms, but none of these therapies is curative. It has been suggested that treatment with neurotrophic factors (NTFs) might protect and prevent death of the surviving dopaminergic neurons and induce proliferation of their axonal nerve terminals with reinnervations of the deafferented striatum.

Dopaminergic differentiation of human mesenchymal stem cells--utilization of bioassay for tyrosine hydroxylase expression.

Parkinson's disease (PD) is a neurodegenerative disorder, caused by a selective loss of dopaminergic neurons in the substantia nigra. In PD, the best therapeutic modalities cannot halt the degeneration. The selective hallmark pathology and the lack of effective treatment make PD an appropriate candidate for cell replacement therapy.

Human mesenchymal stem cells express neural genes, suggesting a neural predisposition.

Because of their unique attributes of plasticity and accessibility, bone marrow-derived mesenchymal stem cells (MSCs) may find use for therapy of neurodegenerative disorders. Our previous studies of adult human MSCs demonstrated that these cells express an extensive assortment of neural genes at a low but clearly detectable level. Here, we report expression of 12 neural genes, 8 genes related to the neuro-dopaminergic system, and 11 transcription factors with neural significance by human MSCs.

Therapeutic potential of neurotrophic factors in neurodegenerative diseases.

There is a vast amount of evidence indicating that neurotrophic factors play a major role in the development, maintenance, and survival of neurons and neuron-supporting cells such as glia and oligodendrocytes. In addition, it is well known that alterations in levels of neurotrophic factors or their receptors can lead to neuronal death and contribute to the pathogenesis of neurodegenerative diseases such as Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, and also aging. Although various treatments alleviate the symptoms of neurodegenerative diseases, none of them prevent or halt the neurodegenerative process.

Embryonic and adult stem cells as a source for cell therapy in Parkinson's disease.

The rationale behind the use of cells as therapeutic modalities for neurodegenerative diseases in general, and in Parkinson's disease (PD) in particular, is that they will improve patient's functioning by replacing the damaged cell population. It is reasoned that these cells will survive, grow neurites, establish functional synapses, integrate best and durably with the host tissue mainly in the striatum, renew the impaired wiring, and lead to meaningful clinical improvement. To increase the generation of dopamine, researchers have already transplanted non-neuronal cells, without any genetic manipulation or after introduction of genes such as tyrosine hydroxylase, in animal models of PD.

Induction of neuron-specific enolase promoter and neuronal markers in differentiated mouse bone marrow stromal cells.

Mesenchymal stem cells in the adult bone marrow are differentiated to connective tissue, muscle, bone, cartilage, and fat cells. Recent studies in cultures, animal models, and humans demonstrated the plasticity of these cells and their capacity to express neuronal markers. However, questions were raised as to whether the neuronal phenotypes reflect transient changes or even fusion with neurons.

Hemin-induced apoptosis in PC12 and neuroblastoma cells: implications for local neuronal death associated with intracerebral hemorrhage.

The exact pathogenesis of neuronal death following bleeding in brain parenchyma is still unknown. Hemoglobin (Hb) toxicity has been postulated to be one of the underlying mechanisms. The purpose of this study was to examine the possible contribution to neurotoxicity of each of the Hb compounds and to characterize the death pathway.