Multiple sclerosis (MS) is an inflammatory disease in which the patient's own immune system attacks and destroys the insulating coating (myelin) of the central nervous system (CNS). After repeated attacks, patients affected by MS experience a progressive loss of physical and cognitive abilities and a subsequent reduction in their quality of life. There is no cure for MS, and disease progression is inevitable. The disease process is driven by both persistent inflammation and a concurrent inability of cells within the CNS to replace damaged myelin (remyelination).
Currently, neural stem cells (NSCs) represent the only therapeutic option capable of counteracting and modulating the plethora of mechanisms that interfere with tissue recovery as evidenced by the encouraging results of a number of experimental cell-based therapeutic studies in varied experimental autoimmune encephalomyelitis (EAE) models, which serve to recapitulate key aspects of MS in rodents/non-human primates. As evidenced by the aforesaid, NSCs possess a therapeutic potential that is distinct from that of small molecules and biologics. While cell replacement was initially considered the most likely therapeutic mechanism of action of NSCs, the vast majority of beneficial outcomes of NSC transplants in EAE seem to be the result of highly sophisticated mechanisms of graft-to-host communication, which take place in vivo. Part drug and part device, stem cells work as biologic disease modifying agents (DMAs) and in so doing sense diverse signals, migrate to specific sites of inflammation/damage within the body, integrate inputs to make decisions, and execute complex response behaviors -- all in the context of specific tissue microenvironments. Clearly, harnessing these unique features will be key in treating a number of disease processes, including the persistent inflammation and the tissue degeneration that occurs in progressive/chronic MS.
While there is strong evidence to support the advantageous effects of NSC transplantation in both acute and chronic animal models of MS, the clinical translation of such promising approaches has yet to be accomplished for a number of significant reasons. One of these is ethical in nature and results from the source of origin of NSCs (fetal or embryonic). A second major issue is the immunogenicity of the allogeneic (i.e., the cells are not of host origin) NSC graft after transplantation. A third is that human fetal NSCs show limited expandability and genotypic stability over the course of extensive passaging in vitro. Therefore, in an effort to overcome these hurdles, we have begun to develop novel approaches to stem cell therapy and have here established an international consortium that is working towards the development of a completely innovative autologous (fibroblasts derived from minimally invasive skin biopsies) directly induced neural stem cell (iNSC)-based therapy for MS patients.
In an effort to accomplish the aforesaid, under the auspices of this project, we will study how iNSCs, obtained from mouse fibroblasts, can affect inflammation and help induce remyelination in pertinent mouse models of MS. By understanding the pathways that drive disease progression and the beneficial actions of iNSCs, we will develop solid preclinical evidence that will facilitate the clinical translation of iNSCs. An autologous (cells from host) source of the stem cells and the availability of preclinical data in informative disease models will open the possibility for a reliable scale-up to patients with progressive MS, who currently do not have any other valuable therapeutic option that modifies disease progression and accumulation of irreversible disability.
We are confident that our efforts will help pave the way for patient-specific stem cell therapies for otherwise incurable neurological diseases that progress due in part to chronic inflammatory responses, which often fail to respond to conventional therapeutic approaches. Beyond the obvious socioeconomic implications, the development of novel safe/reliable translational stem cell medicines in neurology would significantly enhance the quality of life of progressive MS patients and that of their families.