Abstract
Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine.
Highlights
In this review we will focus on antisense oligonucleotides (ASOs), as they are the most clinically developed, with several drugs already approved by the U.S Food and Drug Administration (FDA) and in clinical trials. small interfering RNA (siRNA) and microRNA are inundating clinical pipelines and are proving to be efficacious; they come with specific challenges that will become more evident as we describe ASOs
Nusinersen is a 20 -O-MOE-modified ASO approved by the FDA in 2016 for the treatment of spinal muscular atrophy (SMA), a neuromuscular disorder characterized by weakness in skeletal, bulbar, and respiratory muscles [45]
Results show that the ASO-iLi had a greater accumulation in the body can lead to adverse reactions and hypersensitivity [110,111]
Summary
Oligonucleotide therapeutics have since developed to silence, restore, or modify the expression of disease-causing or disease-associated genes in cancer and genetic disorders [2,3] These therapeutics include antisense oligonucleotides (ASOs), small interfering RNA (siRNA) and microRNA that interfere with coding and noncoding RNA; aptamers and decoys, which rely on their secondary structure to bind to and compromise protein function; and CRISPR/Cas, a promising gene editing technology that directly targets genomic DNA [4,5]. Once bound to the target RNA sequence via Watson–Crick base pairing, the RNA can be degraded, hindered, or manipulated by alternative splicing [6] This makes ASOs more versatile than siRNA or microRNA because ASOs, in addition to reducing protein expression, can enhance target translation. A detailed overview of BP10010 s pre-clinical and clinical data will demonstrate the advances made in liposomal drug delivery and highlight its promising potential in cancer therapeutics
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