ncRNA Strategies for Neurodegenerative Disease: Preclinical Promise and Challenges in Brain Delivery
Background
A literature review published in the International Journal of Molecular Sciences examined both the preclinical promise of strategies targeting non-coding RNA (ncRNA) in neurodegenerative diseases and the challenges of brain delivery and safety. It did not report new experiments or patient treatment outcomes. Drawing on existing literature, the review examined RNA target design, chemical stabilization, and brain delivery technologies.
Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS) involve accumulating neuronal damage. Although ncRNAs do not encode proteins, they regulate gene expression and are therefore attracting attention as candidate targets for intervening in regulatory networks linked to disease pathology. MicroRNAs (miRNAs) contribute to the degradation of target messenger RNAs (mRNAs) or the suppression of protein synthesis, while long non-coding RNAs (lncRNAs) affect gene expression through interactions with proteins, among other mechanisms. A gap remains, however, between identifying a target and developing a safe therapy.
Key findings
The review highlights miR-34a and BACE1-AS as representative targets. It reports that inhibiting miR-34a reduced amyloid-beta formation and tau protein phosphorylation in preclinical models. BACE1-AS is described as an lncRNA that prevents degradation of the BACE1 transcript, thereby increasing expression of an enzyme involved in the pathological cleavage of amyloid precursor protein. Antisense oligonucleotides (ASOs) targeting BACE1-AS are presented as examples of reduced amyloid deposition in preclinical research. Both findings must be distinguished from clinical evidence demonstrating improved cognition or halted disease progression in patients.
Designing a therapeutic candidate and delivering it are separate validation challenges. Computational tools that predict RNA structure and target binding are used to design binding sites and candidate sequences. Chemical modifications are intended to improve molecular stability and binding properties. For example, phosphorothioate modification replaces a non-bridging oxygen in the nucleic acid backbone with sulfur and is presented as a strategy to increase ASO stability. A computationally promising candidate does not automatically guarantee efficacy in vivo.
Lipid nanoparticles (LNPs) and engineered exosomes were also reviewed as RNA delivery vehicles. Exosomes are small vesicles released by cells. Efficiently and safely crossing the human blood–brain barrier (BBB) and achieving even delivery throughout the central nervous system remain key bottlenecks. Exosomes are candidate carriers of therapeutic substances, but they may also contribute to the cell-to-cell transfer of pathological proteins or inflammatory signals, so both their composition and activity require examination.
Implications and outlook
The review emphasizes that developing ncRNA therapies requires assessing target modulation alongside delivery and safety. Because miRNAs regulate multiple genes simultaneously, changing a desired disease pathway may also affect normal functions. Other issues for investigation include concerns about immune responses and liver accumulation with repeated LNP dosing, standardization of exosome isolation procedures, batch-to-batch variability, and large-scale production. The review also notes the difficulty of applying findings from animal models directly to the long-term course of disease in humans.
CRISPR/Cas13, which targets RNA, was discussed as a candidate therapeutic strategy for lowering abnormal ncRNA levels. It acts by cleaving or suppressing RNA and is distinct from base editing, which changes a specific RNA base. Delivering its large components to the brain and maintaining a therapeutic effect also remain unresolved challenges. Halting disease progression is a long-term research goal presented in the paper; the evidence provided does not demonstrate clinical disease arrest or a cure.
These strategies and limitations are described in the full review text on Europe PMC.
Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.
This review offers a framework for assessing both the biological rationale of an ncRNA target and the development feasibility of its delivery vehicle when advancing a candidate into a therapy. For example, developing an ASO targeting BACE1-AS would require evaluating not only reductions in amyloid deposition, but also which brain regions and cells the drug reaches, whether safety is maintained with repeated dosing, and how it affects gene expression in normal tissue. If exosomes are selected as the vehicle, reproducibility of their composition and delivery performance across manufacturing batches is also critical. The review can help organize these development questions, but it does not provide evidence of improved cognition or quality of life in patients.