Limitations and Challenges to Oligonucleotide Therapeutics

Despite their great therapeutic potential, oligonucleotide therapeutics face several limitations or challenges. Some of the major challenges include issues related to toxicity, drug delivery and cellular uptake. Another challenge is degradation by nucleases, particularly of natural oligonucleotides composed of ribose or deoxyribose sugars with a phosphate backbone and bases. Off-target interactions and saturation of endogenous RNA processing pathways are also non-negligible obstacles. To develop oligonucleotide therapeutics, potency, specificity, and efficacious delivery issues must be addressed. Specifically, the following problems must be addressed^[1].

Persistent Gene Silencing

RNA-induced silencing complex is used in the siRNA strategy, which results in persistent post-transcriptional gene knockdown for up to 2-4 weeks. This long-term gene silencing allows siRNA therapeutics to be administered less often. And, without the injection of an antidote, multiple mechanism-based harmful and off-target side effects can last for weeks.

Off-Target Related Toxicities

Off-target toxicities can occur when the oligonucleotide sequence closely matches unintended target sequences, potentially causing off-target effects and downstream changes in gene expression on genes with partial similarity.

Renal Accumulation, Thrombocytopenia, and Inhibition of Coagulation

Some patients undergoing phosphorothioate oligonucleotide therapy have experienced mild to low levels of proteinuria, as well as rare cases of glomerular nephritis. In specific patient groups in clinical trials, some oligonucleotides have been linked to thrombocytopenia. Additionally, certain antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) have exhibited the potential to interfere with blood coagulation mechanisms by triggering the complement cascade and inhibiting the intrinsic clotting pathway.

Oligonucleotide Instability and Delivery-Related Issues

Since oligonucleotides are heavy and negatively charged macromolecules, when administered in their unmodified/naked form, they come across many barriers that hamper their absorption, disposition, and therapeutic activity. Therefore, safe and efficacious delivery remains the greatest challenge to the clinical development of oligonucleotide therapeutics.

Strategies to Overcome the Challenges Faced by Oligonucleotide Therapeutics

To overcome the uptake and delivery problems of oligonucleotide therapeutics, Alfa Chemistry employs a variety of strategies to enhance their stability and facilitate their delivery to target tissues. The following three strategies are widely used.

• Chemical modification
  Chemical modification is one of the most effective ways to improve the delivery of oligonucleotide therapeutics.
• Conjugation and targeting
  Conjugation of oligonucleotide molecules with different chemical moieties can improve the ADMET properties of the oligonucleotide and direct it to the target tissues.
• Delivery vectors
  The properties required in an oligonucleotide can be tailored by formulating targeted advanced delivery vectors.

Note:
ADMET: absorption, distribution, metabolism, excretion, toxicity

Our products and services are for research use only and cannot be used for any clinical purposes.

Online Inquiry

* Name

Phone

* Email

* Services & Products of Interest Limitations and Challenges to Oligonucleotide Therapeutics

Project Description

* Verification Code

Submit