Mesenchymal Stem Cells for the Treatment of MS
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Although, effective immunotherapies for MS exist which downregulate the anti-myelin
      reactivity and reduce the rate of relapses of the disease, there is no effective means today
      to stop the progression of disability and induce remyelination. Neuronal stem cells were
      shown to possess the ability to restore neuronal activity and produce new neurons through
      transdifferentiation. Various other types of stem cells were tested in animal models with
      promising results, revealing a potential for restoration of the neurological function in
      neuroimmune and neurodegenerative conditions. Adult bone marrow derived stromal cells (MSC)
      were shown to induce similar (to neuronal stem cells) immunomodulatory and neuroregenerative
      effects and were shown in our laboratory to induce neuroprotection in the animal model of
      chronic experimental autoimmune encephalomyelitis (EAE). MSCs offer practical advantages for
      clinical therapeutic applications, since they can be obtained from the adult bone marrow and
      therefore the patient can be the donor for himself, without any danger for rejection of the
      cells. In addition, MSCs carry a safer profile and are less prone to malignant
      transformation.

      Our initial clinical experience with 10 patients with ALS and 10 with multiple sclerosis show
      that intravenous and intrathecal administration of MSCs is feasible and safe.

      In this study we propose an explorative protocol with the injection of MSCs (both
      intrathecally and intravenously) in patients with MS, in an effort to prevent further
      neurodegeneration through neuroprotective mechanisms and induce neuroregeneration and
      restoration of neuronal function.

      The primary endpoint will be to further evaluate the safety and feasibility of the treatment
      with MSC infusions, in MS patients. Additionally, the migration ability of the transplanted
      cells will be evaluated by tagging MSCs with the superparamagnetic iron oxide particle
      (Feridex) for detection by MRI. Clinically the patients will be followed by monthly
      evaluations of the MS functional rating scale (EDSS) scale. The MRI, will be also used to
      evaluate changes in the total volume of lesions in the brain and the degree of atrophy.

      Significance: This project may provide information for possible therapeutic uses of this type
      of bone marrow adult stem cells in MS but may also serve as a pilot platform and pave the
      path for future applications of various types of stem cells in neurodegerative diseases, in
      general.
    

Detailed description: 
      This study, is designed as a phase 1/2 open-safety clinical trial. At its first phase, 15
      consenting patients with MS are included.

      Inclusion Criteria:

      Consenting patients fulfilled the following 4 inclusion criteria for this study:

        1. the clinical criteria of Poser et alfor definite MS;

        2. men and nonpregnant women aged 25 to 65 years;

        3. duration of disease longer than 5 years; and

        4. failure to respond to the currently available and registered agents for MS (ie,
           interferons, glatiramer acetate [Copaxone], and immuno-suppressors), as manifested by an
           increase of at least 1 degree in the EDSS score during the past year or the appearance
           of at least 2 major MS relapses during the same period.

      Exclusion criteria:

        1. patients who were treated with cytotoxic medications (ie, cyclophosphamide,
           mitoxantrone, and azathioprine) during the 3 months before the trial;

        2. patients with significant cardiac, renal, or hepatic failure or any other disease that
           may interfere with the ability to interpret the results of the study;

        3. patients with an active infection; and

        4. patients who showed severe cognitive decline or were unable to understand and sign the
           informed consent.

      Bone marrow aspiration is performed under short general anesthesia with puncture from the
      posterior superior iliac crest while the patient was lying in a left or a right lateral
      position. Approximately 200 mL of bone marrow inocula are obtained from each patient.

      MSC Preparation and Culture A culture of purified MSCs is prepared under aseptic conditions
      (positively pressurized clean rooms) using filtered sterilized Dulbecco modified Eagle medium
      with low glucose lev- els (Qiagen, Valencia, California) supplemented with 10% fetal bovine
      serum, 1% L-glutamine, and 1% penicillin-streptomycin- nystatin solution (all from Biological
      Industries, Kibbutz Beit- Haemek, Israel).

      Mesenchymal cells are cultured for 40 to 60 days, until they reach confluency, and then
      harvested and cryopreserved in 10% dimethyl sulfoxide-containing medium in liquid nitrogen
      (-196°C). At 2 weeks, a sample is taken for sterility testing and quality control. After
      sterility confirmed, the MSCs are transferred to the laboratory on dry ice, thawed in a 37°C
      water bath, and washed twice with normal saline solution to remove any residual dimethyl
      sulfoxide. The cells are then resuspended in normal saline at a concentration of 10x106/mL to
      15x106/mL. Two-thirds of the total number of cells (usually 60x106 to 100x106) are injected
      intrathecally, and one-third, intravenously. A sample of the cells to be injected is tested
      by fluorescence-activated cell sorter (FACS) analysis; cells (98%) should express the surface
      markers characteristic of MSCs (CD29, CD73, CD90, CD105, and CD166) and be negative for CD34,
      CD45, and CD14.

      Treatment Protocol All patients receive an intrathecal injection via a standard lumbar
      puncture (mean of 1 million cells per Kg of body weight) and an intravenous injection of
      0.3-1 million cells per kg, intravenously..

      An extension phase is scheduled for patients completing the first phase of this trial as an
      open prospective study with repeated intrathecal or intravenous injections of autologous MSC
      in patients from the initial trial and 10 additional ones (total up to 24 patients) with
      progressive forms of MS (secondary progressive, primary progressive or
      relapsing-progressive). Patients should be defined as failures to first and second lines of
      immunomodulatory treatments experiencing deterioration (at least 0.5 degree in the EDSS
      scale) during the year preceding their inclusion to our study or had at least one major
      relapse without sufficient recovery. Patients will be treated with 1x10 million MSC per kg of
      body weight, intrathecally and intravenously and subsequently with up to 8 courses of IT- or
      IV-injections of MSC (at the same dose), at intervals of 6-12 months. The duration of the
      trial is 4 years.

      Patients will be followed up every 3 months for the whole duration of the trial, for safety
      assessment and changes in the disability scores (EDSS).

      Immunological analysis will be performed at 4 time points (day 1, month 1, month 3 and month
      6) following the first MSC-treatment and will include a fluorescent cell sorter (FACS)
      analysis to evaluate the proportions of the lymphocytes expressing markers of immune
      activation or of regulatory cell phenotype.
    

Intervention name(s): Injection of autologous bone marrow derived mesenchymal stem cells
Intervention type(s): Biological
Intervention description(s): 60 million cells intrathecally (approximately 1 million cells per Kg of body weight) and 20 million cells intravenously
Other intervention name(s): Mesenchymal stem cells of bone marrow
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: multiple sclerosis (MS); bone marrow stromal cells; stem cells