Making Sense of Antisense Oligonucleotide Therapeutics Targeting Bcl-2
Maria Gagliardi1, Ana Tari Ashizawa1
1Bio-Path Holdings, Inc., Bellaire, TX 77401, USA.
Abstract:
The B-cell lymphoma 2 (Bcl-2) family, comprised of pro- and anti-apoptotic proteins, regulates the delicate balance between programmed cell death and cell survival. The Bcl-2 family is essential in the maintenance of tissue homeostasis, but also a key culprit in tumorigenesis. Anti-apoptotic Bcl-2, the founding member of this family, was discovered due to its dysregulated expression in non-Hodgkin's lymphoma. Bcl-2 is a central protagonist in a wide range of human cancers, promoting cell survival, angiogenesis and chemotherapy resistance; this has prompted the development of Bcl-2-targeting drugs. Antisense oligonucleotides (ASO) are highly specific nucleic acid polymers used to modulate target gene expression. Over the past 25 years several Bcl-2 ASO have been developed in preclinical studies and explored in clinical trials. This review will describe the history and development of Bcl-2-targeted ASO; from initial attempts, optimizations, clinical trials undertaken and the promising candidates at hand.
Insights
Targeting B-cell lymphoma 2 (Bcl-2) with antisense oligonucleotides (ASO) offers a promising strategy for cancer therapy. This review details the development of Bcl-2 ASO, from early research to current clinical applications.
Area of Science:
- Molecular Biology
- Cancer Biology
- Pharmacology
Background:
- The B-cell lymphoma 2 (Bcl-2) protein family regulates apoptosis, crucial for tissue homeostasis.
- Dysregulated Bcl-2 expression contributes to tumorigenesis, promoting cancer cell survival and drug resistance.
- Bcl-2 is a validated target for anti-cancer drug development.
Purpose of the Study:
- To review the historical development and advancements of Bcl-2-targeted antisense oligonucleotides (ASO).
- To summarize preclinical and clinical trial progress of Bcl-2 ASO therapies.
- To highlight promising Bcl-2 ASO candidates for cancer treatment.
Main Methods:
- Review of scientific literature on Bcl-2 antisense oligonucleotides.
- Analysis of preclinical studies and clinical trial data for Bcl-2 ASO.
- Synthesis of information on the evolution and optimization of Bcl-2 ASO technology.
Main Results:
- Bcl-2 ASO have progressed from initial concepts to clinical investigations over 25 years.
- Various Bcl-2 ASO have demonstrated specificity and efficacy in preclinical models.
- Several Bcl-2 ASO candidates are advancing through clinical trials.
Conclusions:
- Bcl-2 ASO represent a significant therapeutic strategy in oncology.
- Continued development and optimization of Bcl-2 ASO hold promise for improved cancer treatment outcomes.
- Antisense technology offers a targeted approach to modulating Bcl-2 expression in cancer.
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