Phase I-II Clinical Trial With Autologous Bone Marrow Derived Mesenchymal Stem Cells for the Therapy of Multiple Sclerosis
Phase I-II Clinical Trial With Autologous Bone Marrow Derived Mesenchymal Stem Cells for the Therapy of Multiple Sclerosis
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.
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.
Inclusion Criteria:

 -  Relapsing-remitting MS (RRMS) patients

 -  Age 18-50 years

 -  Disease duration >= 2 and <= 10 years

 -  EDSS: 3.0 - 6.5

 -  1) Patients who do not wish to be subjected to approved immunomodulatory treatments
 (interferon beta and acetato de glatiramer) 2) Patients who have tried and had to
 withdraw within a year due to adverse events 3) Patients who have not responded to
 them after at least 1 year of continuous treatment. Lack of response is considered one
 or more of the following

 -  >= 1 moderate-severe relapses in past 12 months

 -  >= 2 moderate-severe relapses in past 24 months

 -  >= 1 Gadolinium enhancing lesions in a MRI performed in previous 12 months

 Relapse:

 -  Mild: Increase of < 1 EDSS point

 -  Moderate: Increase of >= 1 EDSS point (if baseline EDSS 3.0-5.0) or 0.5 EDSS points
 (if baseline EDSS >= 5.5)

 -  Severe: Increase of >=3 EDSS point

 -  Social, mental and physical ability to communicate with physicians and to understand
 the requirements of the protocol

 -  Has given informed consent to participate in the study

 Exclusion Criteria:

 -  RRMS not fulfilling inclusion criteria

 -  SPMS or PPMSTreatment with any immunosuppressive therapy, including natalizumab and
 fingolimod, within the 3 months prior to randomization

 -  Treatment with any immunosuppressive therapy, including natalizumab and fingolimod,
 within the 3 months prior to randomization

 -  Treatment with interferon-beta or glatiramer acetate within the 30 days prior to
 randomization

 -  Treatment with corticosteroids within the 30 days prior to randomization

 -  Relapse occurred during the 60 days prior to randomization

 -  History of cancer or clinical or laboratory results indicative of severe systemic
 diseases, including infection for HIV, Hepatitis B or C

 -  Pregnancy or risk of pregnancy/ lactation

 -  Current treatment with an investigational therapy

 -  Inability to give written informed consent in accordance with research ethics board
 guidelines