The concept of an Antisense oligonucleotide (an ASO) was first introduced by Stephenson and Zamecnik, who used an antisense nucleotide to stop viral replication in cell culture. The effectiveness of ASOs as treatments has already been seen in other disease, such as Vitravene (or Fomivirsen), which was the first ASO made publicly available, and is used to treat cytomegalovirus retinitis, as well as Isis 3521 which when given to lung cancer patients in addition to combination chemotherapy has been seen to raise life expectancy by as much as 50%. From these past successes, many have hypothesised that they might make an effective treatment for Huntington’s disease (HD) as well, which currently we are only able to treat the symptoms of. In this review, we will be looking at the current attempts to treat HD with ASO technology, he issues that this kind of treatment would face and what we are doing to overcome these issues.
Review and Discussion
An overview of the pathology of Huntington’s disease
Huntington’s disease (HD) is one of the most common genetic disorders affecting our society, believed to affect as many as between 1 or 2 individuals per 20000 people within the population. It is an autosomal dominant genetic disorder, acting at the HTT gene to cause a CAG trinucleotide repeat expansion within exon 1. This expansion raises the number of repeats from the normal 16-20 repeats, to over 35 repeats of the sequence . While the actual cause of HD is not completely understood, it is known that in the mutant form of the HTT gene the protein that it codes for (huntingtin) has a tendency to form cytoplasmic aggregates and nuclear inclusions containing highly ordered amyloid fibres and sequester proteins. The highly ordered amyloid fibres have a low detergent solubility, and the sequester proteins contain transcription and protein quality control factors, and the properties of these molecules imply that the aggregates may well have a significant negative impact on cellular function. Symptoms of HD usually appear in adulthood, causing the death of the individual between 10 and 20 years after the symptoms have appeared. It is defined by dysfunctional neuronal activity, including reduced expression of genes important for Ca2+ homeostasis, neuronal differentiation, survival and transmission, and these symptoms are visible in the sufferer as visible tremors and loss of body control, as well as distinct mood personality change.
The use of antisense oligonucleotides in therapeutics.
Antisense Oligonucleotides (ASOs) in therapeutics is the use of sequences complementary to specific mRNA strands which can inhibit the specific mRNA strand and inhibit its expression. This induces a block in the transfer of genetic information from the DNA to the protein, and so is able to treat diseases with a genetic basis. Antisense oligonucleotides tend to be very short, of between 13 and 25 nucleotides in length, and are relatively cheap to...