RNA Therapeutics for Neurodegenerative Diseases

Neurodegenerative diseases, a class of debilitating conditions characterized by progressive neuronal loss and dysfunction, pose a significant challenge in medicine. Currently available treatments offer limited efficacy, primarily focusing on symptom management. RNA therapeutics, a rapidly evolving field, presents a promising new approach for tackling these devastating illnesses. 

The Underlying Basis for RNA Therapeutics

Neuronal dysfunction in neurodegenerative diseases often stems from aberrant gene expression or the presence of toxic RNA species. RNA therapeutics exploit the body's natural cellular machinery by introducing therapeutic RNA molecules to achieve targeted effects. These molecules can be broadly categorized into two main classes:

  • Small interfering RNAs (siRNAs): These double-stranded RNA molecules silence gene expression by promoting the degradation of specific messenger RNAs (mRNAs). This approach holds promise for targeting genes whose overexpression contributes to neurodegeneration.
  • AAV-mediated gene therapy: Engineered adeno-associated viral (AAV) vectors deliver functional copies of genes directly into neuronal cells. This strategy aims to replace or augment the function of genes mutated or downregulated in disease states.

Mechanisms of RNA therapeutics. Five approaches to how RNA therapy treats diseases are shown in the figure. The first one is that anti-miRNA (A) complements the active chains of the aim miRNA, which weakens the gene silencing effect of endogenous miRNAs and then improves protein expression. Second, miRNA mimics (B) enhance the function of endogenous miRNAs and reduce intracellular protein expression. What's more, block-miRNA agonists (C) are used to prevent RISC from binding to the specific mRNAs by "blocking" miRNA binding sites in order to increase the expression of relevant proteins. Usually, RNA therapy works by utilizing intracellular enzyme RNase H (G) or forming RNA-induced silencing complex (RISC) (D, E1, E2) to cut the targeted mRNA. In plant cells, miRNA bonds with the targeted mRNA completely to degrade it (E1) while in animal cells it cannot complementary to its target mRNA, which blocks ribosomes and reduces translation (E2). ASO is capable of regulating the splicing process of mRNA (F). It corrects wrong splicing by binding to aberrant mRNA splicing sites. Abbreviations: ASO antisense oligonucleotide; dsRNA double-stranded RNA; shRNA short hairpin RNA; pri-miRNA primary miRNA; pre-miRNA pre-cursor miRNA; TRBP Tar RNA binding protein; AGO argonaute; Pol II RNA polymerase II; siRISC siRNA-induced silencing complex; miRISC miRNA-induced silencing complex.

Recent Advancements in Research and Clinical Trials

  • Alzheimer's Disease (AD): Clinical trials are exploring the use of siRNAs targeting BACE1, an enzyme crucial for the production of amyloid beta, a key protein implicated in AD pathogenesis. Additionally, AAV-mediated gene therapy trials are testing the delivery of nerve growth factor (NGF) to promote neuronal survival and function.
  • Parkinson's Disease (PD): Studies are investigating the use of siRNAs to silence the α-synuclein gene, whose protein product forms toxic aggregates in PD. Preclinical research suggests that AAV-mediated gene therapy for enzymes involved in dopamine synthesis may offer a neuroprotective strategy.
  • Amyotrophic Lateral Sclerosis (ALS): Several clinical trials are evaluating the efficacy of siRNAs targeting mutant SOD1, a protein linked to familial ALS.

Obstacles and Future Directions

Despite the encouraging progress, significant challenges remain in translating RNA therapeutics into mainstream clinical practice. Effective delivery of RNA molecules across the blood-brain barrier (BBB) is a critical hurdle. Researchers are developing innovative strategies using nanoparticles and viral vectors to enhance brain bioavailability. Additionally, ensuring long-term expression and minimizing potential off-target effects requires further refinement.

Overcoming challenges in the development of RNA therapeutics. A Common chemical modifications. RNA-based drugs often have various chemical modifications, including 5′-and 3′-end conjugates, 2′-sugar substitution and internucleoside linkage modifications. B Nanocarriers delivery strategies. Five representative nanocarriers are shown: (①) Lipid nanoparticles encapsulating nucleic acids. (②) Cationic polymers electrostatically bind to negatively-charged nucleic acids to form polyplexes. (③) Engineered exosomes with aptamers or therapeutic RNAs on the outer surface. (④) Spherical nucleic acid nanoparticle consisting of an inorganic core coated in densely packed oligonucleotides attached by chemical linkages. (⑤) Self-assembled DNA cage tetrahedron nanostructure. Oligonucleotide drugs can be incorporated into the design of the DNA cage itself. Additional targeting ligands and polyethylene glycol (PEG) can be further conjugated to the nanostructure. These nanocarriers can deliver RNA molecules through binding to the cell membrane, endocytosis, endosome escape and RNAs are released in the cytoplasm and translation to proteins or incorporated into corresponding ribonucleoprotein complexes to silence target transcripts.


RNA therapeutics offer a groundbreaking approach to treating neurodegenerative diseases by targeting the underlying molecular causes. Continued research focused on overcoming delivery challenges and refining therapeutic design holds immense promise for developing effective treatments that can improve the lives of patients suffering from these debilitating conditions.

in News
RNA Therapeutics for Neurodegenerative Diseases
Gen store May 24, 2024
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