Barriers and innovative strategies in miRNA delivery for neurological diseases
| Area of focus | Description | Opportunities | Reference |
|---|---|---|---|
| Targeting neurodegenerative disorders (NDDs) | miRNA-based therapeutics show promise in addressing AD, PD, HD, ALS, Friedreich’s ataxia, SMA, and frontotemporal dementia. These therapeutics aim to replace or inhibit dysregulated miRNAs to provide clinical benefits. | Replacing downregulated miRNAs or inhibiting upregulated miRNAs may be clinically beneficial in NDDs. Development and improvement of synthetic miRNAs, along with specific and effective delivery systems, are needed for this purpose. | [4] |
| Addressing miRNA dysregulation | miRNAs are key gene regulators, playing essential roles in biological and pathological mechanisms; their dysregulation can promote neurological deterioration and the development of NDDs. | Restoring or inhibiting miRNAs altered by disease pathology may treat neurological disorders. Manipulation of endogenous miRNAs or introduction of artificial miRNAs through oligonucleotides or viral vectors could provide effective treatment. | [59] |
| Therapeutic approaches | miRNA-based therapeutics involve using miRNA mimics, siRNAs, inhibitors, and antisense oligonucleotides for treating brain tumors and neurological diseases. Modified oligonucleotides, such as antagomirs or antimirs, can bind and disrupt endogenous miRNAs. | MRX34, a mimic of miR-34a conjugated with liposomes, has entered phase-I clinical trials for liver cancer. LNA-modified oligonucleotides targeting miR-122 delivered intravenously decreased circulating cholesterol levels with no apparent toxicity. Artificial miRNAs can be generated for the repression of specific transcripts. | [124] |
| Delivery techniques | Effective delivery systems are crucial for miRNA-based therapeutics, including viral delivery and administration of modified oligonucleotides. Systemic administration of modified oligonucleotides through intravenous injection or CSF infusion provides a relatively non-invasive and non-toxic means of harnessing miRNAs for therapeutic benefit. | Nanoparticles, exosomes, and viral vectors are being explored for targeted delivery of miRNA therapeutics to the brain. Chemical modifications, such as the fusion of cholesterol, enhance cellular uptake, stability, and integration into the RISC. | [105] |
| Specific miRNA targets | Certain miRNAs, like miR-135, have emerged as therapeutic targets for neurological diseases. Dysregulation of miRNAs, such as miR-30a-5p, may be involved in neurological disorders. | Drugs, including melatonin, can enhance the expression of miR-135 to treat various disease conditions. Morin can inhibit the expression of miR-135 to alleviate different abnormalities. miR-135 plays a role as an endogenous antidepressant in depression, epilepsy, and memory deficits. miR-30a-5p has been shown to inhibit BDNF in the prefrontal cortex, impacting antidepressant effects. | [125] |
| Impact on brain health and disease | miRNAs play major roles in brain tumorigenesis, neurodegenerative diseases, and neurodevelopmental disorders. | miR-135 can act as both an oncogene and a tumor suppressor, depending on the tissue-specific context. miRNAs are dysregulated in stroke and traumatic insults to the CNS. | [125] |
AD: Alzheimer’s disease; PD: Parkinson’s disease; HD: Huntington’s disease; ALS: amyotrophic lateral sclerosis; SMA: spinal muscular atrophy; CSF: cerebrospinal fluid; RISC: RNA-induced silencing complex; CNS: central nervous system; miRNA: microRNA
SP: Conceptualization, Supervision, Validation, Writing—original draft. SM: Visualization, Writing—review & editing.
The authors declare that they have no conflicts of interest.
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