Precision therapeutics and innovative clinical trial design in neurodegenerative diseases

Ariadna Domínguez-García, Juan Carlos Delgado-Uriarte, Amin Cervantes-Arriaga, Precision therapeutics and innovative clinical trial design in neurodegenerative diseases, Revista de Investigación Clínica, Volume 78, Issue 4, 2026, 100050, ISSN 0034-8376, doi:10.1016/j.ric.2026.100050. 

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.

Mitochondria setting the stage for ferroptosis

Ahola S. Mitochondria setting the stage for ferroptosis. Trends in Endocrinology & Metabolism, 2026; 0. Doi:10.1016/j.tem.2026.06.006 

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Recent advances challenge the view of ferroptosis as a predominantly cytosolic process and instead position mitochondria as central regulators of ferroptosis by coordinating iron metabolism, lipid composition, and redox homoeostasis. This review discusses ferroptosis from a mitochondrial perspective and examines its potential relevance to primary mitochondrial diseases, where defects in oxidative phosphorylation profoundly remodel cellular metabolism and redox homoeostasis. The review highlights emerging roles for mitochondrial iron–sulfur cluster biogenesis, coenzyme Q metabolism and trafficking, mitochondrial lipid remodelling, and stress-response signalling in shaping ferroptotic vulnerability. Finally, we discuss current evidence linking ferroptosis to mitochondrial pathology and the therapeutic opportunities arising from targeting ferroptosis pathways in mitochondrial disease.