It seems plausible that one of the first major mainstream areas of development for human gene therapy will involve disabling genes that sustain levels of lipids in the bloodstream. There are a number of credible targets, including those with sizable numbers of human loss of function mutants who seem to do quite well as a result of their mutation: PCSK9, ANGPTL3, ANGPTL4, and ASGR1 for example. Reducing lipid levels in the bloodstream has the effect of slowing the development of cardiovascular disease, reducing the risk of heart attack, stroke, and other related issues. The success of statin drugs is based on exactly this effect, and gene therapies would be much more effective than statins - a one time treatment producing a larger and permenant benefit.
How does this work under the hood? Why does lowering blood lipids - cholesterol, triglycerides, and so forth - have this beneficial result? The primary mechanism of interest relates to the development of atherosclerosis through damaged lipid molecules. The normal operation of metabolism produces reactive molecules that can oxidize lipids, so some small fraction of the lipids in the bloodstream are damaged in this way. With the progression of aging, various forms of cell and tissue damage and their consequences lead to the generation of many more reactive molecules, and thus greater numbers of damaged lipid molecules entering the bloodstream - the problem becomes worse over time. You might look at the progression of cause and effect that starts with mitochondrial DNA damage, for example, but there are also more systemic issues such as chronic inflammation, which goes hand in hand with greater levels of oxidative damage.
Oxidized lipids can irritate blood vessel walls, giving rise to a feedback loop of inappropriate cellular reactions that produce inflammation and draw in ever more immune cells to try to clean up the mess. Many of these cells die, overwhelmed by forms of oxidized lipid that mammalian biochemistry is not well equipped to handle. The result is a growing, fatty plaque of dead cells and harmful lipids, the signature of atherosclerosis. These plaques weaken and narrow blood vessels, and eventually something ruptures or a blood vessel is blocked - an occurrence that is often fatal, and at best disabling. Interfering in this feedback loop at any point can slow it down: cut down the amount of all lipids entering the bloodstream, make immune cells more resilient or capable, or remove just the problem lipids through some other mechanism.
I think that the latter two are better than the former, as they can in principle be made close to 100% efficient without altering the way in which cellular metabolism functions in ways that are yet to be fully understood over the long term, as is the case for dramatic reductions in blood lipid levels. It isn't the case that all lipids can be removed from the bloodstream, and it isn't the case that all oxidative damage can be prevented. In general, periodic repair is a good deal more useful than partial prevention, as repair can help those already damaged and in late stages of disease. Still, we'll be getting a more effective implementation of the worse option in the near future, it seems, as that is where the bulk of the attention is focused.
Consider this scenario: it's 2037, and a middle-aged person can walk into a health centre to get a vaccination against cardiovascular disease. The injection targets cells in the liver, tweaking a gene that is involved in regulating cholesterol in the blood. The simple procedure trims cholesterol levels and dramatically reduces the person's risk of a heart attack. Although antibody-based therapies have been launched to help those most at risk, the cost and complexity of the treatments means that a simpler, one-off fix such as a vaccine would be of benefit to many more people around the world.
The good news is that a combination of gene discovery and the blossoming of genome-editing technologies such as CRISPR-Cas9 has given this vision of a vaccine-led future for tackling heart disease a strong chance of becoming reality. The breakthrough came in 2003, when researchers investigated three French families with members who had potentially lethal levels of low-density lipoprotein (LDL) cholesterol and who harboured a mutation in the gene PCSK9. PCSK9 encodes an enzyme that regulates levels of LDL - or 'bad' - cholesterol. Sensing the possibilities, investigators sought to determine whether naturally occurring mutations in PCSK9 could also have the effect of lowering LDL cholesterol. After combing the data from about 3,600 individuals who provided a blood sample, the researchers sequenced DNA from the 128 participants with the lowest levels of LDL cholesterol. They discovered that about 2% of African-American participants had one broken copy of PCSK9. A follow-up study of a different, larger population similarly found mutations in almost 3% of African Americans, which was associated with an 88% reduction in the risk of ischaemic heart disease.
The liver is a preferred target organ of gene therapy for companies such as Editas Medicine, Sangamo Therapeutics, and CRISPR Therapeutics; it is straightforward to deliver genes to the liver, and the CRISPR-Cas9 tool is especially efficient in the organ, editing a greater proportion of cells than it does in most other tissues. The liver is also an excellent place from which to tackle cholesterol - it clears LDL cholesterol from the blood and is also a main engine of lipid synthesis. Researchers have shown that more than half of Pcsk9 genes in the mouse liver could be silenced with a single injection of an adenovirus containing a CRISPR-Cas9 system directed against Pcsk9. This led to a roughly 90% decrease in the level of Pcsk9 in the blood and a 35-40% fall in blood LDL cholesterol.
The approach is "absolutely plausible, even feasible", from a technological point of view. But there is also a philosophical barrier to negotiate. "You don't necessarily want to treat people who haven't got a disease yet." Others go further. "Changing lifestyle may be much more effective for a population than focusing on high-cost interventions." They worry that a gene therapy for individuals at high risk would hinder efforts to help people to help themselves. "It is the way the human mind works. Take a pill and we think we are protected."
There is certainly a reluctance to follow through in permanent gene therapies for prevention and enhancement at the moment - the work could be proceeding much more rapidly than it is, given the rapidly falling costs of genetic biotechnology. It will probably require more adventurous groups such as BioViva Sciences or Ascendance Biomedical to break down that door by simply going ahead and offering the gene therapies that are technologically plausible outside the mainstream regulatory system. These treatments will initially have a low effectiveness, in terms of the proportion of cells transfected by the therapy, but that is a challenge that will be solved with increasing efficiency over the next decade. Someone has to get started, go first, show the way. If regulatory systems as they presently exist make that hard, then the start will occur outside the regulatory framework, just as it did for stem cell therapies - and a good thing too, as that is pretty much the only circumstance that might help to make current medical regulation less oppressively terrible.