Aug 2026· Disease-a-month : DM· pp.
102210
· 0 citations· 207 references
Medicine
TL;DR
Current advances in the therapeutic landscape of progressive MS are summarized, highlighting recently approved treatments as well as promising agents under clinical investigation, with particular emphasis on the underlying mechanisms of action of these therapies and their potential to modify disease progression, restore neural function, and support the development of personalized treatment strategies for patients with PMS.
Abstract
Progressive multiple sclerosis (PMS) represents a severe and disabling form of MS characterized by a gradual accumulation of neurological impairment and limited responsiveness to conventional disease-modifying therapies. Unlike the relapsing forms of the disease, progressive MS is driven not only by peripheral immune dysregulation but also by persistent neuroinflammation, microglial activation, mitochondrial dysfunction, and progressive neurodegeneration within the central nervous system. These complex and overlapping pathogenic mechanisms contribute to irreversible axonal loss and pose significant challenges for therapeutic intervention. Although recent advances in immunomodulatory treatments have improved outcomes for some patients, currently available therapies provide only limited benefits in slowing disease progression. Consequently, the identification of novel molecular pathways and therapeutic targets has become a major focus in the development of more effective strategies for progressive MS. Rapid progress in understanding the cellular and molecular basis of disease progression has facilitated the exploration of innovative therapeutic approaches, including targeted immunotherapies, neuroprotective agents, remyelination-promoting strategies, and emerging cell-based interventions. Here, in this review, we summarize current advances in the therapeutic landscape of progressive MS, highlighting recently approved treatments as well as promising agents under clinical investigation. Particular emphasis is placed on the underlying mechanisms of action of these therapies and their potential to modify disease progression, restore neural function, and support the development of personalized treatment strategies for patients with PMS.
Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterised by inflammation, demyelination, and progressive neurological dysfunction within the central nervous system. Current diagnostic approaches, including magnetic resonance imaging, cerebrospinal fluid analysis, and evoked potentials, provide valuable insights but remain limited by insufficient specificity in early detection. In parallel, therapeutic strategies are constrained by the blood–brain barrier (BBB), which restricts efficient drug delivery to affected neural tissues. Recent advances in nanotechnology have introduced theranostic nanocarriers as a promising platform that integrates targeted drug delivery with real-time disease monitoring. Additionally, the integration of artificial intelligence (AI) has accelerated the optimisation of nanoparticle design, improved diagnostic accuracy through advanced imaging analysis, and enabled predictive modelling of disease progression. This review explores the pathophysiology and current diagnostic landscape of MS, and highlights the role of AI in nanomedicine and neurology, emphasising its potential to enhance personalised treatment strategies and real-time monitoring.
Radwan Ahmed, Mohsen Ayman Al-Jazzar, Maha Nasr· Science and Technology Nexus· 0 citations
Multiple Sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder of the Central Nervous System (CNS) that affects more than 2.8 million people worldwide. It is recognized as one of the leading causes of non-traumatic neurological disability among young adults. It is an inflammatory demyelination disease with axonal damage and progressive neurological disability, which creates high personal, social, and economic costs. The development of neuroimaging, immunobiology, and molecular biology has significantly enhanced the accuracy of diagnosis, disease monitoring, and therapeutic development, enabling earlier intervention and better relapse management with disease-modifying therapeutic agents. These innovations have improved clinical training, retention, and optimization of treatment for relapsing forms of the disease. The Pathophysiology of MS is complex, and the factors that lead to the condition are a complicated interplay of genetic risk, environmental exposure (Epstein-Barr virus, vitamin D deficiency, and smoking), and impaired immunological responses. Despite these gains, there are some significant limitations. There are limited therapeutic interventions that are effective against progressive multiple sclerosis; remyelination failure still plays a role in irreversible disability. Predicting treatment response in this disorder is yet to be identified. The existing literature has identified gaps in understanding immune dysregulation, neurodegeneration, and new modulators, including viral exposures, the gut microbiota, and cell signalling pathways. These unaddressed gaps impede the design of individual and neuroprotective therapeutic approaches that can modify the disease course over the long term. This review critically examines the recent developments and current issues in multiple sclerosis, including etiology and Pathophysiology and diagnostic and therapeutic interventions, with a particular focus on highlighting critical areas of knowledge gaps as well as future research directions that may be used in support of multidisciplinary and integrative approaches to enhance the quality of life and multiple sclerosis clinical outcomes in patients.
K. Ravi, K. Arora· Current Neurovascular Resear...· 0 citations
Key therapeutic approaches discussed include gene-silencing technologies such as antisense oligonucleotides, RNA interference, and CRISPRCas9- based strategies, as well as small-molecule modulators targeting mutant huntingtin aggregation, proteostasis, autophagy, mitochondrial dysfunction, and neuroinflammation.
B. Semwal, Kuldeep Singh, Ritesh Sharma et al.· Current Pharmaceutical Biote...· 0 citations
Progressive multiple sclerosis (MS) remains a major therapeutic challenge because disability often continues to accumulate despite effective control of relapses and new focal inflammatory lesions. This dissociation suggests that progression is driven not only by acute inflammation, but also by a distinct process increasingly termed smoldering neuroinflammation. Recent evidence supports chronic active lesions as an important but non-exclusive pathological substrate of this process. These lesions are characterized by persistent lesion-edge inflammation, slowly expanding tissue injury, iron-laden myeloid cells, astrocyte–immune crosstalk, and incomplete repair. Importantly, this inflammatory activity is not restricted to isolated white matter plaques, but is spatially compartmentalized across the central nervous system, involving interactions among white matter lesions, meninges, cortex, and subcortical regions. Advances in susceptibility-based MRI and PET imaging now allow in vivo assessment of imaging-related correlates of this otherwise hidden pathology, including paramagnetic rim lesions (PRLs), slowly expanding lesions (SELs), and TSPO-PET-defined inflammatory activity. Although these biomarkers overlap only partially, they provide complementary insights into lesion composition, structural expansion, and metabolic inflammation. Accumulating studies further suggest that current disease-modifying therapies incompletely control established chronic lesion biology, while other inflammatory-independent or age-related neurodegenerative processes may also contribute to progression. In this review, we discuss the pathological basis, imaging correlates, and therapeutic implications of smoldering neuroinflammation in progressive MS.
Min Wang, Bo-Chi Zhu, Xi-Jing Mao· Frontiers in Immunology· 0 citations
A lysosome-centered framework for understanding PGRN-related neurodegenerative pathologies is presented, and TMEM106B is discussed as a critical genetic modifier within this lysosomal network, highlighting its role in shaping disease risk and phenotypic heterogeneity.
