The unravelling of the human genome provided the potential for a huge number of new drug targets. While much of the talk has proved to be more hype than hope, much research is going on into nucleotide drugs for genetic targets. Very few have thus far reached the market, but many potential nucleotide-based treatments are in development.
Many exploit antisense technology, where a short fragment of single-stranded RNA, complementary to a messenger RNA (mRNA) transcribed in a cell, binds to the mRNA, thus blocking translation and, essentially, turning the gene off. The potential of this approach was first shown in the late 1970s, and the first antisense drug – Isis’s fomivirsen (Vitravene) – was licensed by the FDA in 1998 for cytomegalovirus retinitis. This remained the only approved antisense drug until the start of 2013, when the company’s mipomersen (Kynamro) got the go-ahead.
Mipomersen is a second-generation antisense oligonucleotide designed to treat the rare genetic disorder homozygous familial hypercholesterolaemia, a condition that affects only around 300 people in the US. According to Mary McGowan, who was at the time of the trials at the Concord Hospital Cholesterol Treatment Center in New Hampshire and is now a senior medical director at Genzyme (which collaborated with Isis on the project), people with the disorder can take the maximum possible dose of statins in combination with other cholesterol-lowering agents, and still have a low-density lipoprotein cholesterol level in excess of 400. This rises to 1000 or more if untreated.
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