Why Fat Stem Cells for Multiple Sclerosis?
Multiple sclerosis is an autoimmune disease in which the patient’s immune system begins attacking the lining of the nerves called the myelin sheath.
There are two main problems that need to be addressed in MS: a) how to stop the misdirected immune attack and b) how to repair the damage that has already been caused.
Currently available therapies are directed towards non-specifically suppressing the immune system so that ongoing nervous system destruction is prevented. The drawback being that immune suppression exposes the patient to various other pathogens.
Mesenchymal stem cells (MSC) have been demonstrated in numerous animal models and clinical trials to inhibit pathological immune responses while stimulating regeneration of damaged nerve tissue. In clinical trials, bone marrow derived MSC have passed Phase I safety studies and are currently in a number of Phase II and III efficacy studies.
Stemnow.com offers the therapy using the patient’s own fat derived cells which contain not only MSC but also several therapeutic cell populations.
Background: In healthy people, the immune response is fine-tuned so as to specifically be able to destroy foreign pathogens, while at the same time have the ability to know that it should not turn against the body. For reasons that are not completely understood, some patients developed “autoimmune” diseases in which the immune system starts attacking tissues of the body. In multiple sclerosis this is manifested through destruction of the myelin sheath that insulates nerves in the white matter of the brain. This destruction is observed by MRI in the form of plaques, and functionally is manifested by the patient experiencing the various characteristics of MS ranging from visual (e.g. optic neuritis, nystagmus, etc), motor (e.g. paresis, spasticity, etc), sensory (e.g. paraesthesia), balance (e.g. ataxia, vertigo) and cognitive (depression, cognitive dysfunction) alterations.
There are 4 main types of MS: 1) Relapse-remitting MS is the condition which the majority (about 85-90%) of MS patients are initially diagnosed with. As the name indicates, this type is characterized by relapses followed by periods of remission in which disease activity subsides. It is believed that during remission the oligodendrocytes “fix” the neurons by producing new myelin; 2) Secondary progressive MS usually occurs as a progression of the relapse remitting type at the point where remissions decrease in frequency and eventually the debilitating characteristics continually progress. On average it takes about 19 years for MS to convert from relapse-remitting to secondary progressive; 3) Primary progressive is characterized by patients presenting with MS in which no remissions are seen; and 4) In the progressive relapsing form, a continuous increase in symptoms is seen, however spikes of accelerated disease activity are interspersed in the progression of the condition.
Depending on the type of MS, various treatments are routinely used. These include steroids, immune suppressants (cyclosporine, azathioprine, methotrexate), immune modulators (interferons, glatiramer acetate), and immune modulating antibodies (natalizumab). The general treatment concept is to rapidly treat relapses so as to minimize permanent damage, as well as to prevent onset of relapse or progression to more advanced forms of MS. Unfortunately long term efficacy data is not available for many of the current approaches used clinically. At present none of the MS treatment available on the market selectively inhibit the immune attack against the nervous system, nor do they stimulate regeneration of previously damaged tissue. Experimental approaches in clinical trials are trying to use a peptide vaccine to specifically inhibit anti-myelin immune responses by the company BioMS, however even if successful this approach will not induce regeneration. Other experimental approaches include the use of bone marrow stem cells in combination with chemotherapy to destroy the original immune system of the patient and subsequently attempt to restart it. Needless to say this procedure has the possibility of adverse effects. We use another type of stem cell therapy that does not involve chemotherapy or destruction of the immune system, instead it involves a “re-education” through administration of mesenchymal stem cells that concurrently inhibit pathological immunity while stimulating regeneration of damaged neural tissue.
Rationale: Mesenchymal stem cells are a type of cell that possesses potent immune regulatory activity. It has been demonstrated in clinical trials that patients suffering from deregulated immune responses, such as in Crohn’s Disease or Graft Versus Host Disease go into remission after administration of mesenchymal stem cells (www.osiris.com).
Unlike conventional immune suppressive drugs that act everywhere in the body, mesenchymal stem cells possess the ability to “home” to areas of inflammation and specifically shut off immune responses that are harming the body. Various molecules secreted by injured tissues such as FGF-2 are known to chemoattract mesenchymal stem cells. Additionally, during pathological immune responses, such as in multiple sclerosis, the molecule interferon gamma is produced. Mesenchymal stem cells “sense” interferon gamma production and become more immune suppressive in response to it (Ryan et al. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol. 2007 May 22).
One way that mesenchymal stem cells locally shut down pathological immune responses is through blocking T cell proliferation. This occurs through a variety of mechanisms, one being activation of the immune suppressive enzyme indolamine 2,3 deoxygenase (Meisel et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004 Jun 15;103(12):4619-21).
Additionally, mesenchymal stem cells are known to induce generation of an immune suppressive population of T cells called T regulatory cells (Maccario et al. haematologica 2005; 90(4). These cells are known to protect the body against autoimmunity and act in a specific manner to inhibit pathological but not healthy immune responses. Specific inhibition of pathological immunity in mouse models of multiple sclerosis has also been reported by mesenchymal stem cells (Zappia et al. Blood, 1 September 2005, Vol. 106, No. 5, pp. 1755-1761).
In addition to blocking such autoreactivity, mesenchymal stem cells have been demonstrated to:
a) Accelerate remyelination (Keilhoff et al. Transdifferentiated mesenchymal stem cells as alternative therapy in supporting nerve regeneration and myelination. Cell Mol Neurobiol. 2006 Oct-Nov;26(7-8):1235-52);
b) Prevent neuronal apoptosis (Caplan et al. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006 Aug 1;98(5):1076-84);
c) Directly differentiate into neurons (Muñoz-Elías et al. Marrow stromal cells, mitosis, and neuronal differentiation: stem cell and precursor functions. Stem Cells. 2003;21(4):437-48)
d) Induce endogenous neural stem cells activation to regenerate new neurons (Caplan et al. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006 Aug 1;98(5):1076-84).
Since mesenchymal stem cells promote nervous system repair through several synergistic mechanisms, these cells possess a much higher probability of success as opposed to other gene or cytokine therapies in which only one reparative mechanism is being activated. In fact, these cells are known to produce a wide number of trophic growth factors themselves which assist in neural regeneration.
Clinical Implementation: The dual role of mesenchymal stem cells for blocking pathological immunity while inducing regeneration of neural tissue that has already been damaged has already been described (Uccelli et al. Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection. Expert Opin Biol Ther. 2006 Jan;6(1):17-22). Animal studies and case reports are supportive of this approach. In fact, a clinical trial is currently ongoing at the University of Cambridge utilizing mesenchymal stem cells for multiple sclerosis. We have treated numerous patients with mesenchymal stem cells with no evidence of adverse events or immune reactions. Some of the patient experiences in our hands can be seen in our recent publication.