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Published on: February 1, 2019
Making sense of antisense
Laura Vidal1, Sarah Blagden, Gerhardt Attard
1Centre for Cancer Therapeutics, Institute of Cancer Research, Royal Marsden Hospital, Sutton, Surrey SM2 5PT, London, United Kingdom.
Abstract:
The specific and rational targeting of key genes, identified to be vital to driving cancer growth, has recently led to the successful development of several small molecule and antibody therapeutics. However, despite considerable efforts, antisense oligonucleotides (ASO) have yet to prove their worth as targeted therapies. However, many important genes cannot be readily targeted by antibodies or small molecules, and could be blocked by ASOs. Moreover, the latest generation of ASOs is safe, well tolerated and able to modulate target protein expression both in surrogate and tumour tissue in the clinic. This review will describe the experience acquired with these agents to date and will raise critical issues relevant to the further optimal development of these agents. Future clinical studies need to evaluate combinations of several different ASO targeting multiple key targets, including strategies that reverse functional redundancy of the key target (e.g., targeting several Bcl family members including Bcl-2 and Bcl-x). Approaches to maximise the duration of target blockade yet avert the need for prolonged intravenous infusions, with the consequent risk of line infection and thrombosis, are also needed. These may include slow-release depot subcutaneous formulations. Short interfering (Si) RNA therapeutics, which are now being evaluated in early clinical trials, are also envisioned to impact the future utility of this class of therapeutics. The high manufacture cost of these agents, when compared with small chemical molecules, could however, limit their success unless cost-effective manufacturing processes are developed.
Insights
Antisense oligonucleotides (ASOs) show promise for targeting genes inaccessible to other therapies. Further development requires combination strategies and novel formulations to optimize cancer treatment.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Targeted gene therapies, including small molecules and antibodies, have advanced cancer treatment.
- Antisense oligonucleotides (ASOs) offer a potential approach for targeting genes resistant to conventional therapies.
- The latest generation of ASOs demonstrates safety and efficacy in modulating protein expression in clinical settings.
Purpose of the Study:
- To review the clinical experience with antisense oligonucleotides (ASOs) as targeted cancer therapies.
- To identify critical issues and future directions for the optimal development of ASO therapeutics.
- To explore the potential of ASOs and short interfering RNA (siRNA) in cancer treatment.
Main Methods:
- Review of clinical data and literature on antisense oligonucleotide (ASO) applications in cancer therapy.
- Analysis of challenges and opportunities for ASO development, including combination strategies and drug delivery.
- Discussion of emerging RNA interference (RNAi) therapeutics like short interfering RNA (siRNA).
Main Results:
- Antisense oligonucleotides (ASOs) can effectively target previously undruggable genes in cancer.
- Current ASO technology is safe and well-tolerated, with proven ability to reduce target protein levels.
- Short interfering RNA (siRNA) therapeutics are emerging as a complementary approach in early clinical trials.
Conclusions:
- Future clinical studies should investigate ASO combinations to overcome target redundancy and enhance efficacy.
- Development of novel drug delivery systems, such as subcutaneous formulations, is needed to improve ASO treatment duration and patient compliance.
- Addressing manufacturing costs is crucial for the broader success of ASO and siRNA therapeutics in oncology.
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