Abstract
Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.
Highlights
Neurodegenerative diseases are a range of conditions that are characterized by the progressive functional and structural degeneration of the central or peripheral nervous system, and the patient’s cognitive ability and athletic ability are severely impaired, placing a huge burden on the individual’s family and society [1]
Antisense oligonucleotides (ASOs) are single-stranded oligonucleotides of 8 to 50 bases in length that bind to selected RNA sequences and regulate the expression of genes by several mechanisms depending on their chemical properties and targets, which will affect protein synthesis at posttranscriptional processing or protein translation levels [11]
Gapmer ASO was designed with two RNA arms modified with resisting nucleases and enhancing affinity of complementary sequences located on either side of the central 8–10 base DNA “gap,” which serves as a substrate for RNase H to induce targeted cleavage of mRNA and results in protein translation inhibition (Figure 1) [16,17,18]. e pathological feature of many neurodegenerative diseases is the accumulation of toxic proteins, in which many are caused by genetic mutations
Summary
Neurodegenerative diseases are a range of conditions that are characterized by the progressive functional and structural degeneration of the central or peripheral nervous system, and the patient’s cognitive ability and athletic ability are severely impaired, placing a huge burden on the individual’s family and society [1]. Neurodegenerative diseases comprise a set of over 600 diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), ALS, and multiple sclerosis (MS) [2,3,4]. Several biological characteristics, such as mitochondrial dysfunction, oxidative stress, abnormal protein accumulation, trophic factor deficiency, and inflammatory response, are accompanied by these diseases, but the pathogenesis is still too complex and diverse to be fully elucidated. If ASOs are used to treat neurodegenerative diseases, they must be stable in the body and enter the central nervous system cells to target the causative genes. We will mainly discuss the development of antisense nucleic acid drugs in three neurodegenerative diseases—SMA, DMD, and ALS
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