Stem Cell and Gene Therapeutic Strategies for the Treatment of Multiple Sclerosis

Abstract

Multiple sclerosis is a disease of the central nervous system that predmoninantly affects young adults. The pathogenic mechanisms are complex, however numerous studies indicate that the disease is initiated by an autoimmune attack on protein targets present in the central nervous system. Given that a dysfunctional immune system perpetuates the pathophysiological mechanisms that characterize this inflammatory disorder, several therapeutic approaches that target immune cells or their secreted mediators have been generated and are currently used clinically. Although these strategies have been partially beneficial to a proportion of patients, current therapies are not particularly effective at preventing disease progression. As such there is a large and unmet need for the development of more effective treatments. Owing to a number of promising results obtained in mouse models of multiple sclerosis, cell therapies implementing hematopoietic, mesenchymal and neural stem cells may provide practical vehicles for in situ immunomodulation, neuroprotection and regeneration. In concert with these approaches, gene therapy strategies are being investigated to restore antigen-specific tolerance or to deliver anti-inflammatory molecules. Furthermore targeted delivery of glial or neurotropic factors, which counteract the activity of inhibitory molecules within the neurodegenerative component of the lesion, is also being pursued. It is conceivable that these experimental approaches alone, or in combination with emerging and current treatments, may establish a rational protocol for the treatment of multiple sclerosis and potentially other autoimmune disorders.

Targeting VIP and PACAP Receptor Signalling: New Therapeutic Strategies in Multiple Sclerosis

“…Although the agent(s) that initiate disease onset have not been clearly elucidated, several lines of evidence, derived from the EAE (experimental autoimmune encephalomyelitis) model, support that the disease is autoimmune in nature, regulated by APCs (antigen-presenting cells) and auto-reactive Th1 and Th17 cells (Steinman, 2001; Sospedra and Martin, 2005; Korn et al, 2009). These cell types co-ordinate the production of inflammatory cytokines and chemokines within the CNS parenchyma, leading to the recruitment of macrophages, mast cells, neutrophils, CD8 + T-cells and B-cells, which subsequently attack components of the CNS, including the myelin sheath and axons (Siatskas and Bernard, 2009). The accumulation of axonal damage leads to a permanent loss of neurological function (Lassmann et al, 2007).…”

A Consensus Statement Addressing Mesenchymal Stem Cell Transplantation for Multiple Sclerosis: It’s Time!

“…Although the agent(s) that initiate disease onset have not been clearly elucidated, the current prevailing hypothesis suggests that the disease is autoimmune in nature, regulated by autoreactive T helper (Th) 1, Th17 cells and antigen presenting cells (APCs) [1][2][3]. These cell types co-ordinate the production of inflammatory cytokines and chemokines within the central nervous system (CNS) parenchyma, leading to the recruitment of macrophages, mast cells, neutrophils, CD8 + T cells and B cells, which subsequently target components of the CNS, including the myelin sheath and axons [4,5]. Given that the pathological hallmarks of MS include an overactive immune response, strategies for the treatment of MS have focused on suppressing inflammation, which should indirectly prevent CNS damage at least in the initial phases of the disease.…”

“…Given that the pathological hallmarks of MS include an overactive immune response, strategies for the treatment of MS have focused on suppressing inflammation, which should indirectly prevent CNS damage at least in the initial phases of the disease. To this end, a number of current therapies that collectively target inflammatory cells in acute relapses either by, suppressing cell function, limiting the entry of cells into the CNS or altering the immune response, are in clinical practice [5]. Whilst having moderate success in slowing disease progression in~30% of relapsing-remitting MS patients, the fact remains that these treatment modalities do not cure the disease [6].…”

Gene-modified mesenchymal stromal cells: A VIP experience

“…In fact for some applications, the use of MSCs-conditioned media has a similar effect compared to the inoculation of MSCs 23,24) . Therefore, improving/increasing the production of factors involved in its therapeutic activity should be an easy and effective way to increase its potency 25,26) (Fig. 1).…”