Jul 2026· Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion· Vol 78 4, pp.
100050
· 0 citations· 106 references
Medicine
TL;DR
This review summarizes emerging therapeutic approaches, including monoclonal antibodies targeting protein aggregation, immune-modulating and metabolic interventions, antisense oligonucleotides, gene replacement and genome-editing strategies, stem cell-based therapies, and neurosurgical delivery platforms and neuromodulation technologies.
Abstract
Neurodegenerative diseases are biologically heterogeneous disorders characterized by progressive neuronal dysfunction, overlapping molecular pathologies, and limited disease-modifying therapies. Advances in biomarker development, molecular staging, and precision medicine are reshaping therapeutic strategies and clinical trial design across Parkinson's disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, and related disorders. This review summarizes emerging therapeutic approaches, including monoclonal antibodies targeting protein aggregation, immune-modulating and metabolic interventions, antisense oligonucleotides, gene replacement and genome-editing strategies, stem cell-based therapies, and neurosurgical delivery platforms and neuromodulation technologies. It also examines evolving clinical trial methodologies such as biomarker-enriched recruitment, adaptive and delayed-start designs, platform trials, decentralized models, and master protocols. Additional emphasis is placed on diagnostic biomarkers, multimodal artificial-intelligence pipelines, systems-biology perspectives, network-based therapeutic strategies, and the reproducibility and interpretability requirements for computational tools. Despite recent progress, major challenges remain, including biological heterogeneity, limited translatability of preclinical models, delivery barriers, long-term safety concerns, and inequities in access to biomarker-based care and trial participation. Future directions will require combination therapies, integrated biomarker pipelines, preventive strategies, and pragmatic trial systems capable of translating biological advances into durable and equitable clinical benefit.
A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.
Nagaraj Rangappa, Riddhi Upadhyay, Nathish Lakshman et al.· Advances in Protein Chemistr...· 0 citations
Huntington's disease [HD] is a progressive, autosomal dominant neurodegenerative disorder caused by a pathogenic CAG repeat expansion in the HTT gene, resulting in mutant huntingtin [mHTT] protein accumulation, neuronal dysfunction, and selective neurodegeneration. Current pharmacological management remains largely symptomatic, with no approved therapies capable of modifying disease progression. In recent years, however, significant advances in molecular neuroscience and translational medicine have accelerated the development of disease-modifying strategies targeting the underlying pathogenic mechanisms of HD. This review synthesizes emerging pharmacological therapies with a particular focus on insights derived from recent and ongoing clinical trials. 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. In addition, advances in symptomatic treatments addressing motor, cognitive, and psychiatric manifestations are reviewed. The article critically examines translational challenges encountered in clinical development, including blood-brain barrier penetration, allele selectivity, dosing paradigms, patient heterogeneity, biomarker integration, and ethical considerations associated with irreversible genetic interventions. Lessons learned from both successful and failed trials highlight the importance of precision medicine approaches, biomarker-guided trial designs, and combination therapies targeting multiple pathogenic pathways. Collectively, this review provides an updated and clinically relevant overview of the evolving HD therapeutic landscape and outlines key considerations for translating molecular advances into effective and safe pharmacological interventions.
B. Semwal, Kuldeep Singh, Ritesh Sharma et al.· Current Pharmaceutical Biote...· 0 citations
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that places an increasing burden on patients, caregivers, and healthcare systems worldwide. Current disease-modifying therapies (DMTs) are limited by high costs, complex administration, and reliance on advanced biomarker infrastructure, highlighting the shortcomings of existing treatment paradigms. These limitations have sparked growing interest in gene- and nucleic acid-based interventions as upstream strategies to modify AD pathogenesis. Among these, small interfering RNA (siRNA) is especially compelling because it can be rationally programmed, directed at multiple molecular pathways, and paired with rapidly evolving delivery technologies. However, the clinical translation of siRNA therapies for AD is still constrained by challenges in brain-targeted delivery, safety, and sustained efficacy. In this review, we summarize current concepts in AD pathology, highlight recent clinical and translational advances, and critically assess emerging brain-targeted siRNA delivery platforms and their key bottlenecks. Within a precision-medicine framework, brain-targeted siRNA offers the possibility of aligning patient selection, molecular targets, and delivery strategies with biomarker-defined AD endotypes. We discuss both the therapeutic promise and the realistic limitations of siRNA-based approaches for AD, outline priorities for future development, and identify key gaps that must be addressed to enable meaningful clinical implementation.
In the context of global ageing, the prevalence of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is rapidly increasing. However, current symptomatic treatments have achieved limited benefits in clinical settings and fundamentally fail to reverse the progressive loss of specific neuronal populations. Halting neurodegeneration and restoring impaired cognitive, motor or visual functions through nerve regeneration and circuit reconstruction represent the clinically meaningful goals for treatments of NDDs. Regenerative medicine has emerged as a promising paradigm to address this unmet need. In this review, we trace the historical evolution of regenerative therapies for NDDs - from early exploratory cell transplantation to modern approaches involving pluripotent stem cells (PSCs) and in vivo direct reprogramming. Furthermore, we elucidate the core strategies of regenerative medicine within an integrated framework encompassing "Replacement", "Regeneration", and "Rejuvenation". Finally, we highlight recent advances in clinical research, particularly milestone trials in cell replacement therapy for PD, as well as the application of mesenchymal stem cells (MSCs) in AD and ALS.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multifactorial pathology, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction. Despite extensive research, currently approved treatment provides only symptomatic relief, while recently approved disease-modifying monoclonal antibodies have shown limited benefits. Ongoing clinical investigations have shifted toward multi-target directed ligands (MTDLs), RNA-based therapies, immunotherapies, and vaccines. Some approved drugs that have established safety profiles are being repurposed to address the disease's neuropsychiatric symptoms or modulate AD pathological changes. Integrating diverse pharmacophores, such as curcumin, resveratrol, chromone, and indole, within a single skeleton is anticipated to exert multi-modal modifying properties. In parallel, optimization of ADME properties, particularly blood-brain barrier (BBB) permeation and efflux modulation, remains a major obstacle in AD drug design. The incorporation of artificial intelligence (AI) and machine learning (ML) is expected to enhance the prediction of pharmacokinetic, pharmacodynamic, and toxicity parameters.
Sana Saffour, Turgut Seckin Gul, H. Gul· Future Medicinal Chemistry· 0 citations
Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease (AD), yet no effective disease-modifying therapy is currently available. Its pathogenesis is highly complex, involving multiple interacting pathological processes, which poses substantial challenges for therapeutic intervention. Moreover, PD often has a prolonged prodromal phase and lacks sufficiently sensitive and specific diagnostic methods for early-stage detection, further limiting timely identification and treatment. Current pharmacological therapies mainly provide symptomatic relief, but their long-term use is frequently associated with reduced efficacy and motor complications. Therefore, the development of novel therapeutic strategies and potential disease-modifying agents remains an urgent priority. This review systematically summarizes the molecular mechanisms and biomarkers associated with PD, outlines current symptomatic treatments, and discusses emerging therapeutic candidates in clinical development, with particular emphasis on disease-modifying strategies. By integrating pathogenic mechanisms, diagnostic advances, and therapeutic progress, this review aims to provide a comprehensive perspective to support the development of more effective interventions for PD.
Zhihui Shen, Jiaxin Cheng, Linlin Wang et al.· Current Neuropharmacology· 0 citations
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