Multiple sclerosis (MS) is a chronic debilitating demyelinating disease of the central nervous system (CNS) which affects over 700,000 people in Europe with a total annual health care cost of €27.3 billion (Ernstsson et al., 2016). Current therapeutic strategies offer modest or ephemeral relieve of MS symptoms. However, they fail to modify disease progression. As a result, there is currently no licensed disease-modifying therapy for MS (Hauser & Cree, 2020). Inflammation is a common pathological feature of MS (Calabrese et al., 2015; Milstein, Barbour, Jackson, Kosa, & Bielekova, 2019). In particular, the inflammatory insult that drives the pathology becomes condoned off behind an intact blood-brain barrier (BBB) during MS progression. This leads to a clinical scenario where the delivery of antibody-based therapeutics is extraordinarily challenging and ineffective due to the inability to cross the non-compromised BBB (Matthews, 2019).
In the last 15 years, some studies showed the critical role of extracellular matrix (ECM) in the development and homeostasis of the CNS (Aleithe et al., 2019; Back et al., 2005; Crapser et al., 2020). The main components of neural ECM include chondroitin sulphate proteoglycans, tenascin-R and hyaluronic acid, which are synthesized by both neurons and glial cells (Srivastava, Sherman, & Back, 2020). These molecules are regulated in physiological conditions, shaping both neuronal and glial functions through a multitude of molecular mechanisms. The upregulation of some particular ECM molecules by reactive astrocytes during neuroinflammation and neurodegeneration results in the formation of growth-impermissive environment and impaired synaptic plasticity. Some authors also described the fact that ECM molecules have a neuroprotective effect, at least in the form of perineuronal nets. All this data suggests that targeting expression of specific ECM molecules may lead to the development of new therapeutic strategies promoting regeneration and synaptic plasticity (Song & Dityatev, 2018)
Changes in ECM content and metabolism have been related to several pathological conditions, including stroke, traumatic injury and MS, and these changes disrupt repair by endogenous neural stem cells.
Herein, we set out for the first time to test address local delivery of an ECM scaffold into the CNS that could downregulate neuroinflammation associated to the disease. We hypothesized that an external ECM source would lead to a downregulating of the astrogliosis generated after MS-like induction reducing its severity and decreasing the incidence of the disease. This will also avoid the ECM deposition and scar generation in the demyelinated axons, allowing oligodendrocytes to remyelinate the injured axons after the MS inflammatory insult.
