Aljasir MA. An Integrated Network Biology and Molecular Dynamics Approach Identifies CD44 as a Promising Therapeutic Target in Multiple Sclerosis. Pharmaceuticals. 2026;19:254.
Background: Multiple sclerosis (MS) is a neuroinflammatory disease characterized by autoimmune-driven inflammation in the central nervous system that damages axons and destroys myelin. It is difficult to diagnose multiple sclerosis due to its complexity, and different people may react differently to different treatments. While the exact cause of multiple sclerosis (MS) and the reasons for its increasing prevalence remain unclear, it is widely believed that a combination of genetic predisposition and environmental influences plays a significant role. Methods: Finding biomarkers for complicated diseases like multiple sclerosis (MS) is made more promising by the emergence of network and system biology technologies. Currently, using tools like Network Analyst to apply network-based gene expression profiling provides a novel approach to finding potential medication targets followed by molecular docking and MD Simulations. Results: There were 1200 genes found to be diferentially expressed, with CD44 showing the highest degree score of 15, followed by CDC42 and SNAP25 genes, each with a degree score of 14. To explore the regulatory kinases involved in the protein-protein interaction network, we utilized the X2K online tool. The present study examines the binding interactions and the dynamic stability of four ligands (Obeticholic acid, Chlordiazepoxide, Dextromethorphan, and Hyaluronic acid) in the Hyaluronan binding site of the human CD44 receptor using molecular docking and molecular dynamics (MD) simulations. Docking studies demonstrated a significant docking score for Obeticholic acid (-6.3 kcal/mol), underscoring its medicinal potential……. Conclusions: This integrated method underscores the significance of dynamic validations for dependable drug design aimed at CD44 receptor-mediated pathways. Future experimental techniques are anticipated to further hone these findings, which further advance our understanding of putative biomarkers in multiple sclerosis (MS).
This says CD44 is a target for therapy in MS. Who’d have thunk it?
Brennan FR, O’Neill JK, Allen SJ, Butter C, Nuki G, Baker D. CD44 is involved in selective leucocyte extravasation during inflammatory central nervous system disease. Immunology. 1999; 98:427-35. doi: 10.1046/j.1365-2567.1999.00894.x.
Clinical signs of experimental autoimmune encephalomyelitis (EAE) are associated with the selective recruitment of CD4+ memory (CD45RBlow CD44high) T cells into the central nervous system (CNS). However, we have found that many of these recently recruited memory cells are CD44low, suggesting that the CD44 antigen may be involved in, and transiently lost during, the extravasation process. Indeed, administration of a CD44-specific antibody (IM7.8.1) induced leucocyte CD44 shedding and both prevented the development and ameliorated the severity of established EAE by inhibiting mononuclear cell infiltration into the CNS. Trafficking of cells into lymph nodes, however, a property mainly of naïve cells, was essentially unaffected. In contrast, treatment with antibody to very late activation antigen-4 (VLA-4) prevented homing to both the CNS and to lymph nodes. This study contests previous reports that dismissed a role for CD44 in inflammation of the CNS (Yednock et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992;356:63-6) and, coupled with observations in murine dermatitis and arthritis, suggests that CD44 is involved in the homing of primed lymphocytes to sites of inflammation. CD44 should therefore be considered a target for immunotherapy of T-cell-mediated inflammatory diseases, such as multiple sclerosis.
In Yednock et al they came up with CD49d/alpha4 integrin as a target for blocking white cell trafficking the brain….This led to the development of natalizumab. They dismissed CD44, because rather than blocking binding to blood vessels it seemed to increase it and the reason is simple CD49d is present on the white cells but not the blood vessel hence antibodies block binding of CD49d to VCAM-1 on the blood vessel, but CD44 is present not only the white cell but also the lesion so as the antibodies have two CD44 binding sites they cross link the white cells to the vessel wall giving the impression that it was not important. Wrong. So over 25 years later anti-CD44 sounds interesting…Maybe we were ahead of our time.
However blocking CD44 will probably cause PML and as it is probably better than anti-CD49d (natalizumab) at blocking migration of cells into the brain so maybe it was a good idea that blocking anti CD44 never caught on all those years ago.
Source: multiple-sclerosis-research.org