Multiple Sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS), which affects young individuals during the most productive phases of their lives. In 85% of the patients, MS initially presents with a relapsing-remitting clinical course (relapsing-remitting MS, RRMS), which in the majority of these individuals is followed by a progressive stage with irreversible accumulation of neurologic deficits (secondary progressive MS, SPMS). A subset of patients develops a primary progressive variant of MS (PPMS), in which chronic accumulation of disability without super-imposed relapses is the most prominent clinical feature. Especially for chronic stages, only limited therapeutic options are available to date.
Moreover, in recent years both incidence and prevalence of MS have increased for yet unknown reasons, strengthening the need for efficacious therapies targeting acute and progressive stages in MS. Indeed, in spite of treatment strategies available already, the majority of MS patients will develop relevant neurological deficits over the course of the disease. As such, recent studies have shown that about 30-50% of MS patients will develop walking impairment over the course of 25 years of MS. Given that the age of onset in MS is between 20 and 30 years of age in most patients, this poses a relevant burden and threat to MS patients and their families, but also society in general. In particular, our understanding of the underlying pathology in progressive stages of MS is still limited, which has also hampered the development of novel therapeutics to causally influence these stages of the disease.
Given the increasing incidence of MS and our limited therapeutic options for progressive MS stages outlined above, developing novel strategies to tackle acute and particularly chronic MS stages in order to prevent disease progression is of utmost importance both for individual patients as well as for society, since available treatments, rehabilitation costs as well as the risk of unemployment pose relevant risks both for patients and society.
From a pathophysiological standpoint, local anti-inflammatory and regenerative mechanisms limit the acute inflammatory processes and define the extent of tissue recovery and consecutive residual neurological deficits both during acute and progressive disease stages, but fail over time causing progressive disease worsening. Astrocytes are CNS resident cells with important roles during both stages of MS. Their actions can either favor chronification or promote resolution of the inflammatory processes. We and others have identified several mechanisms, by which secreted factors from astrocytes promote the ongoing immune response. Even though astrocytes also secrete tissue-regenerative factors such as the leukemia inhibitory factor (LIF) or epidermal growth factor (EGF), the translation of these factors into translationally relevant strategies has been challenging due to an incomplete understanding of their cellular targets and molecular regulation. Thus, the discovery of novel tissue-protective factors and the understanding of their regulation in acute and chronic stages of MS yields the potential to develop novel therapies for chronic inflammatory and degenerative diseases of the CNS.
In this context, we have discovered a novel potential protective factor secreted from astrocytes, the so-called Heparin-binding EGF-like growth factor (HB-EGF). Our preliminary experiments have determined that HB-EGF is efficient in the initial stages to limit autoimmune CNS inflammation, but fails over time due to epigenetic alterations in its promoter region, which limit its availability and function. This process might contribute to disease progression, which makes HB-EGF and its regulation a potential treatment target in MS.
Our overall aim within this project therefore is to (i) examine role and (ii) regulation of HB-EGF in acute and progressive stages of autoimmune CNS inflammation for tissue recovery. In a more translational part of the project, we next aim to determine (iii) the potential therapeutic value of HB-EGF and its epigenetic regulation in acute and chronic autoimmune inflammatory CNS diseases. Finally, we aim to (iv) determine and its relevance as novel biomarker in MS, which might help to stratify patients at risk for disease progression.
