This antisense drug[68] was licensed for use by the US Food and Drug Administration in January 2013. It is only licensed for patients who suffer from the most severe form of familial hyper-cholesterolaemia. One of the reasons this drug has been successful enough to reach the market (albeit at the eye-watering cost of over $170,000 per year per patient{402}) is because the gene that it targets is expressed in — yes, you guessed it — the liver. A downside to this, however, is that there have been liver toxicities reported with the use of this drug. The Food and Drug Administration has demanded that Sanofi (who bought Genzyme) must monitor liver function of all patients.{403} The European Medicines Agency refused to license the drug at all, citing safety concerns.{404}
The hundreds of millions of dollars that Isis received from Genzyme for its antisense therapy is a lot of money. Yet consider this. It took over twenty years to move from the basic research to a marketed drug, and the whole process cost over $3 billion.{405} That’s an awfully big investment to recoup.
Of course, pioneering drugs, especially those which use a relatively untried type of molecule, would be expected to take a long time and a lot of money to develop. The hope is always that later programmes are able to run faster and more smoothly. Certainly, clinical trials for therapies based around junk DNA are building in number. There is a human smallRNA that is co-opted by a virus to help it infect cells. In an example of using junk to fight junk, an antisense drug is in phase II clinical trials, targeting this smallRNA.{406}
But here’s an odd thing to consider. In 2006 the pharmaceutical giant Merck paid over a billion dollars for a company that was developing smallRNAs as therapeutics. In 2014 it sold the company on, for a fraction of what it paid.{407} Another company, Roche, stopped its own efforts in this research area in 2010.
There has recently been a big upsurge in investment into biotech companies working on smallRNAs. RaNA Therapeutics, which is believed to be developing RNA-based drugs that will prevent the interaction of long non-coding RNAs with the epigenetic machinery, raised over $20 million in 2012.{408} Dicerna, which is developing smallRNAs against some rare diseases and oncology indications, raised $90 million in 2014.{409} That’s the third set of financing it has received, despite having no programmes that have reached clinical trials yet.{410}
Yet here’s the weird thing. Literally as I write this chapter, in spring 2014, an alert comes up in my email account and tells me that Novartis has decided to slow down dramatically its research on this topic.{411} The pharma giant mainly cited the ongoing problems with working out how to deliver smallRNAs to the right tissues. This has been the biggest issue with these therapeutics since companies first started trying to develop them. Many of the companies in the junk RNA field have been set up by brilliant scientists, but that doesn’t mean that any of the basic drug delivery problems will just disappear overnight. Not all the companies will fail. But quite a lot of them probably will. There haven’t been any major breakthroughs on this problem, and certainly nothing that would explain why investors are pouring money into new biotechs in this area.
One day science will probably be able to interpret all the possible epigenetic modifications that are found in the genome and predict precisely what their consequences will be for gene expression. We’ll work out how to capture carbon, and how to establish colonies on Mars. Tuberculosis will be a distant memory and we’ll all have a good grasp of the Higgs boson. But unravelling the reasons behind the triumph of hope over experience in the investment community? Be realistic.
20. Some Light in the Darkness
As we near the end of our wanderings through the darker regions of our genome, the more alert reader may remember that we haven’t addressed the mystery of one of the human disorders first encountered at the beginning of this book. This condition is the cumbersomely named facioscapulohumeral muscular dystrophy, or FSHD. This is the condition in which there is wasting of the muscles of the face, shoulders and upper arms.
It occurs when patients inherit a smaller number of a particular genetic repeat on one of their copies of chromosome 4. Even quite a few years after the mutation was identified, the reason why this caused disease remained mysterious, because there just didn’t seem to be a protein-coding gene anywhere near the genetic defect.
We finally have an understanding of how the disease symptoms are caused and the story is remarkable. It pulls together a number of the themes we have already encountered, showing how junk DNA, epigenetics, genetic fossils and abnormal RNA processing all work together to create an extraordinary tale of pathological conspiracy.{412}
Let’s recap a little. On normal copies of chromosome 4, a region is repeated between eleven and 100 times. This region is just over 3,000 base pairs in length. In people with FSHD, there is a much smaller number of repeats — between one and ten units — on one of their copies of the chromosome.
Here’s where the first complication arises. There are people who have ten or fewer copies of this unit, but who don’t have FSHD. Their muscles are completely healthy. The low number of repeats only causes a problem if it occurs on a copy of chromosome 4 that also contains another feature.
To understand the importance of this other feature, we need to look in more detail at what is found in the repeating units. They all contain a retrogene.[69] A retrogene is a form of junk DNA. It is created when the messenger RNA from a normal cellular gene gets copied back into DNA and reinserted into the genome. It’s very similar to the process we saw in Figure 4.1 (page 38) and occurred long ago in human evolution.
Because retrogenes are originally created from messenger RNA templates, they often don’t include the proper regulatory sequences of normal genes. They won’t contain splicing signals (because the messenger RNA template had already been spliced before it was copied into DNA) and they lack appropriate promoter and enhancer regions. But some can still be used to produce messenger RNA. This is the case with the FSHD retrogene, but it doesn’t usually matter, because the RNA doesn’t function properly in the cell. It doesn’t contain the correct signals for adding a string of A bases to the end of the messenger RNA, the process described in Figure 16.5 (page 233). Because of this, the messenger RNA is unstable and doesn’t get used as a template for production of protein.
But, when a person has only a small number of FSHD repeats, and other sequences on chromosome 4 are present, the final copy of the FSHD retrogene can be spliced to an additional sequence. This creates a signal at the end of the messenger RNA which allows the cellular machinery to add A bases. This in turn stabilises the messenger RNA, and it is transported to the ribosomes to act as the template for production of a protein — a protein that should never be switched on in mature muscle cells.
The FSHD protein is one that regulates the expression of other genes by binding to specific DNA sequences. It is usually only expressed in the germline, the cells that produce eggs or sperm. There is no definitive explanation yet for why expression of this protein causes muscle wasting, and it may be that a number of mechanisms are involved. It may activate genes that trigger muscle cell death. It may cause loss of muscle stem cells, perhaps by activating other retrogenes and genomic invaders that should be kept silent. One intriguing possibility is that the muscle cells that express the FSHD protein are destroyed by the patient’s own immune system.