Chemistry, structure and function of approved oligonucleotide therapeutics

27 September 2024 Articles ، Muthiah Manoharan Oligonucleotide therapeutics chemistry and function ، Antisense oligonucleotides and RNA interference ، Approved oligonucleotide drugs for genetic diseases ، Splice-switching oligonucleotides and their mechanism ، LNP and GalNAc delivery systems in RNA therapy ، MOE-RNA and phosphorothioate modifications in ASOs ، Future of gene silencing therapies with oligonucleotides

1. Introduction

In the past 25 years, 18 oligonucleotide-based therapies have been approved to treat diseases like Spinal Muscular Atrophy (SMA), Duchenne Muscular Dystrophy (DMD), and hereditary transthyretin-mediated amyloidosis. These therapies function via various mechanisms, including:

Antisense Oligonucleotides (ASOs)
Splice-Switching Oligonucleotides (SSOs)
RNA Interference (RNAi)
RNA Aptamers

2. Historical Background

The origins of oligonucleotide therapeutics trace back to the 1950s and 1960s with foundational discoveries in DNA and RNA synthesis. Key pioneers, such as Todd and Khorana, contributed to understanding genetic coding, paving the way for molecular biology and nucleic acid-based medicine.

3. First-Generation Modifications

Early oligonucleotides incorporated chemical modifications such as 2′-fluoro-RNA, 2′-O-methyl RNA, and phosphorothioates (PS).
These changes enhanced stability and improved target affinity.
The first FDA-approved antisense drug, VITRAVENE, emerged from these advances.

4. Second-Generation Modifications

The development of 2′-O-(2-methoxyethyl)-RNA (MOE-RNA) led to improved metabolic stability and efficacy. Key drugs developed with this technology include:

KYNAMRO (for hypercholesterolemia)
SPINRAZA (for spinal muscular atrophy)
TEGSEDI (for hereditary amyloidosis)

5. Mechanisms of Action

ASOs: Block gene expression by binding to complementary RNA.
SSOs: Modify RNA splicing to correct genetic errors.
RNAi: Uses siRNA to silence genes.
Aptamers: Bind to proteins to modulate their function.

6. Delivery Challenges and Solutions

Lipid nanoparticles (LNPs) enable efficient RNAi drug delivery.
GalNAc conjugation enhances uptake in liver cells.

7. Future Prospects

Research continues on next-generation chemical modifications and targeted delivery mechanisms. New developments in receptor/ligand targeting may expand oligonucleotide therapies beyond liver tissues.

Conclusion

Oligonucleotide therapeutics continue to revolutionize medicine, with new chemical modifications and delivery strategies driving success. Their impact on treating genetic disorders remains a beacon of hope for future advancements.