Phase I-II Clinical Trial With Autologous Bone Marrow Derived Mesenchymal Stem Cells for the Therapy of Multiple Sclerosis
Condition: Relapsing Remitting Multiple Sclerosis (RRMS)
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Immunomodulatory therapies to treat the relapsing-remitting phase of multiple sclerosis (MS)
      are designed to ameliorate the inflammatory processes that mediate the damage to the central
      nervous system (CNS) and to delay progression of the disease. To date, there is no effective
      means to stop the progression of disease and induce remyelination. Adult stem cells therapy
      show great promise and is rapidly developing as alternative therapeutic strategy. We propose
      the use of bone marrow-derived autologous Mesenchymal (BM-MSC) Stem Cells transplantation to
      treat patients with relapsing-remitting MS (RRMS), despite immunomodulatory therapy. Taking
      advantage of the potential that MSC possess strong immunomodulatory properties thought to
      play a role in the maintenance of peripheral tolerance and in the control of autoimmunity and
      that may stimulate repair and regeneration of lesions, we plan a trial of a single injection
      of autologous BM-MSC into eight patients. First, we aim to assess the feasibility, safety and
      tolerability of autologous MSC therapy in RRMS. Second, we plan to evaluate the effects of
      BM-MSC transplantation on MS disease activity by clinical, neurophysiological, immunological
      and imaging assessments. Autologous MSC will be obtained from bone marrow aspirates, purified
      by culture and characterized by surface antigen expression. A single dose of autologous
      BM-MSC will be injected intravenously. Clinical, neurological and immunological assessments
      will be scheduled at baseline (before BM-MSC transplantation) at 1, 3, and 6 months after
      transplant. The imaging will be performed at 3 and 6 months after transplant. Proposed trial
      will enable us to ascertain whether autologous BM-MSC transplantation is a feasible and safe
      procedure, and whether BM-MSC can establish an environment of immune tolerance and through
      the local production of neurotrophic/growth factors, might induce neuroprotection and
      improvement in CNS function.
    

Detailed description: 
      Multiple sclerosis (MS) is a chronic, demyelinating disease of the CNS. Onset typically
      occurs in early adulthood. Patients present with intermittent symptoms that are partially
      reversible; this form is termed relapsing-remitting (RRMS). Over time, most patients develop
      secondary-progressive MS (SPMS) which manifests as irreversible and gradual neurological
      impairments that often progress without acute relapses. Beta-interferons or glatiramer
      acetate represents the first line therapeutic option for RRMS. Clinical trials confirm that
      show partial efficacy, though they do not prevent the onset of secondary progression. SPMS,
      is the consequence of axonal loss and neurodegeneration and no current therapy has been
      effective. Stem cell therapy show great promise and is rapidly developing as alternative
      therapeutic strategy. Clinical indications for adult stem cells, which can be safely
      harvested and normally behave well without formation of tumours, are rapidly increasing. The
      majority of human stem cell trials have focused on clinical applications for haematopoietic
      stem cells (HSC), mesenchymal stem cells (MSC), or both, which can be easily obtained in
      clinically sufficient numbers from peripheral blood, bone marrow, adipose tissue, or
      umbilical cord blood and placenta. MSC can readily be isolated from a small sample of bone
      marrow and rapidly expanded so as to generate large numbers of cells for autologous
      therapies. When administered intravenously have an immune suppressive effect that can
      ameliorate animal autoimmune diseases. MSC transplantation significantly improves clinical
      outcome in experimental allergic encephalitis (EAE), the animal model of MS. When
      intravenously injected, MSC may migrate to inflammatory brain lesions and promote survival of
      brain-resident cells. Several disease models demonstrate axonal neuroprotection following MSC
      therapy, with some evidence that this is potentially mediated through the production of
      neurotrophic/growth factors, and/or immunomodulatory effects of MSC. For that reasons, MSC
      have become the focus of research as a potential cell therapy for inducing neuroprotection in
      human neurodegenerative diseases such as MS.

      A growing body of literature confirms the therapeutic MSC biological properties, and provide
      a plausible mechanism of action to guide clinical trial design with a number of phase I/II
      trials in MS patients now underway. Experimental clinical trials in MS are being considered
      or have recently been initiated by several research groups, which are testing the therapeutic
      potential of different sources of MSC. Learning from previous clinical studies, and taking
      advantage of the potential that adult BM-MSC may stimulate repair and remyelination, to plan
      a clinical trial in patients with inflammatory MS seems reasonable. We propose a safety trial
      of a single intravenous injection of autologous bone marrow-derived MSC into 8 subjects with
      RRMS. The trial proposed here will enable us to ascertain whether autologous BM-MSC
      transplantation is a safe procedure, and whether BM-MSC therapy during the
      relapsing-remitting phase of MS can establish a immunomodulatory and regenerative
      microenvironment and reverse neurological disability in RRMS patients.
    

Intervention name(s): Bone marrow autologous mesenchymal stem cells transplantation
Intervention type(s): Biological
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: multiple sclerosis; mesenchymal stem cells; autologous transplantation; MRI efficacy; clinical safety