Heart disease

Putative medicines that mimic mutations

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Molecules that block the activity or production of the protein ANGPTL3 have now been found to lower blood levels of lipoproteins and cholesterol in mice and healthy humans, mimicking the protective effects of genetic mutations in ANGPTL3.

Blood triglyceride levels are measured in millions of people each day as part of routine clinical practice1. Triglycerides, which are the body's main form of fat, act as a proxy for blood levels of triglyceride-rich lipoproteins (TRLs) — the form in which these molecules, along with cholesterol, are transported in the circulation. Higher levels of triglycerides confer a greater risk of heart attack, but it has been unclear whether lowering blood levels of TRLs would reduce the risk. Writing in the New England Journal of Medicine, Dewey et al.2 and Graham et al.3 report that genetic or pharmacological inactivation of the protein angiopoietin-like 3 (ANGPTL3) in humans and mice can lower not only blood levels of TRLs but also the risk of heart attack. These results set the stage for randomized controlled trials of ANGPTL3 inhibition.

TRLs are secreted by the liver into the bloodstream, where the triglycerides they carry are broken down by the enzyme lipoprotein lipase in a process called lipolysis, releasing fatty acids that are stored in fat or used by muscle for fuel. Further metabolism of TRLs leads to the production of low-density lipoproteins (LDLs), which carry predominantly cholesterol. Cholesterol from TRLs and LDLs can be deposited in blood vessels, leading to build-ups called plaques (Fig. 1). This phenomenon, known as atherosclerosis, can restrict blood flow and increase the risk of a heart attack.

Figure 1: Triglyceride-rich lipoproteins and the risk of heart attack.

Triglyceride-rich lipoproteins (TRLs), which contain triglyceride and cholesterol molecules, are synthesized by the liver and secreted into the bloodstream. An enzyme called lipoprotein lipase that is anchored to the inner lining of the blood vessel breaks the triglycerides in TRLs into fatty acids (among other products), which are used by muscle for fuel or by fat cells for storage. This process leaves cholesterol-rich TRLs, which can deposit cholesterol in blood vessels as plaques, a phenomenon called atherosclerosis. Further metabolism leads to the production of low-density lipoproteins (LDLs), which also deposit atherosclerotic plaques in blood vessels. High levels of TRLs or LDLs and the presence of atherosclerosis both confer an increased risk of heart attack. The protein ANGPTL3 inhibits lipoprotein lipase. Dewey et al.2 and Graham et al.3 demonstrate that inhibiting ANGPTL3 activity in mice and humans reduces levels of TRLs and LDLs.

Epidemiological studies have found an association between blood lipoprotein concentrations and the risk of heart attack4, and human genetic studies and randomized trials suggest that LDL is one causal factor5. Some evidence, particularly analyses of proteins that clear TRLs from the blood, suggests that TRLs also contribute to the risk of heart attack4.

Which of the several human proteins involved in TRL clearance could be targeted by drugs to improve established treatments for preventing heart attack? Over the past decade, identifying rare genetic mutations that protect people against disease has emerged as a powerful strategy for making such decisions6. As an example, consider the gene PCSK9, which encodes an enzyme involved in cholesterol homeostasis7.

About 1 in 40 African Americans carries a mutation that inactivates one of their two copies of PCSK9. Individuals who carry such mutations have lower-than-average levels of LDL cholesterol8 in their blood and are protected against heart attack. Several healthy people who lack both copies of PCSK9 have also been identified, increasing the likelihood that inhibition of PCSK9 is safe9. These observations inspired the development of medicines that mimic human PCSK9 mutations, and such PCSK9 inhibitors have been shown in clinical trials to lower LDL cholesterol levels and decrease the risk of heart attack10.

Dewey et al. took a similar tack, but focused on the ANGPTL3 gene. The ANGPTL3 protein is synthesized by the liver and secreted into the bloodstream11. It inhibits lipoprotein lipase12, thus delaying clearance of TRLs from the blood and increasing TRL blood concentrations (Fig. 1). These observations from mice suggested that complete lack of ANGPTL3 should lead to lower levels of TRLs and LDLs. In support of this idea, a family has been identified13 whose members have exceptionally low levels of TRLs and LDLs in their blood as a result of the complete absence of ANGPTL3.

Dewey and colleagues sequenced ANGPTL3 in more than 58,000 people, and found that mutations that led to ANGPTL3 deficiency were associated not only with lowered blood lipoprotein levels, but also with a 41% decrease in the risk of atherosclerotic cardiovascular disease, including heart attack. The researchers' finding is in agreement with a separate report14 published this year. In addition, the authors of that earlier report used a computed tomographic technique to visualize blood vessels around the hearts of three people who had complete absence of ANGPTL3, and detected no atherosclerosis. Collectively, these data provide confidence that pharmacological inhibition of ANGPTL3 might, by decreasing atherosclerotic plaques, reduce the risk of heart attack.

Armed with these facts, Dewey et al. and Graham et al. took different pharmacological approaches to inactivate ANGPTL3. Dewey and colleagues used an antibody to inhibit the protein's activity, whereas Graham and co-workers made use of short nucleotide sequences called antisense oligonucleotides, which they designed to bind to and inhibit translation of ANGPTL3 messenger RNA.

The groups first turned to various mouse models engineered to be at increased risk of atherosclerotic plaques. Inactivation of ANGPTL3 by either method led to smaller areas of atherosclerosis than did a control treatment. In addition, Graham et al. observed other benefits, including reduced triglyceride levels in the liver (indicative of triglycerides being more efficiently processed) and improvements in the response to insulin.

Next, Dewey et al. treated healthy humans (who had no ANGPTL3 deficiency) with the antibody. The treatment resulted in a dose-dependent reduction in triglyceride and LDL cholesterol levels. Graham and colleagues found a similar effect when treating healthy volunteers with their antisense oligonucleotide. No serious adverse events were reported with either treatment.

These two reports add to the growing evidence that, beyond levels of LDL cholesterol, enhancing clearance of TRLs is a key route to combating heart attack. There are seven genes in which rare mutations are known to protect against heart attack, and in four of these, the protective mutations seem to work by improving clearance of TRLs15. Therefore, strategies that enhance TRL breakdown, including by inhibiting ANGPTL3, are likely to be a fruitful therapeutic approach.

However, several barriers remain before these ANGPTL3 inhibitors can be developed for clinical use. First, large randomized controlled trials are still required to prove that these therapeutics will reduce the risk of heart attack without significant toxicity. Second, it remains uncertain how much clinical benefit ANGPTL3 inhibition will provide, when added to current standard practice for people at risk. Finally, the expense of antibodies targeting PCSK9 has hampered their uptake (they are estimated16 to cost about US$14,000 a year); it remains to be seen how cost will affect inhibitors of ANGTPL3. But if these hurdles can be overcome, TRLs could make the transition from being used as a test for heart- attack risk to being a target for treatment.Footnote 1


  1. 1.

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  1. 1

    Stone, N. J. et al. Circulation 129, S1–S45 (2014).

  2. 2

    Dewey, F. E. et al. N. Engl. J. Med. 377, 211–221 (2017).

  3. 3

    Graham, M. J. et al. N. Engl. J. Med. 377, 222–232 (2017).

  4. 4

    Musunuru, K. & Kathiresan, S. Circ. Res. 118, 579–585 (2016).

  5. 5

    Goldstein, J. L. & Brown, M. S. Cell 161, 161–172 (2015).

  6. 6

    Harper, A. R., Nayee, S. & Topol, E. J. Nature Rev. Genet. 16, 689–701 (2015).

  7. 7

    Abifadel, M. et al. Nature Genet. 34, 154–156 (2003).

  8. 8

    Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr & Hobbs, H. H. N. Engl. J. Med. 354, 1264–1272 (2006).

  9. 9

    Zhao, Z. et al. Am. J. Hum. Genet. 79, 514–523 (2006).

  10. 10

    Sabatine, M. S. et al. N. Engl. J. Med. 376, 1713–1722 (2017).

  11. 11

    Koishi, R. et al. Nature Genet. 30, 151–157 (2002).

  12. 12

    Shimizugawa, T. et al. J. Biol. Chem. 277, 33742–33748 (2002).

  13. 13

    Musunuru, K. et al. N. Engl. J. Med. 363, 2220–2227 (2010).

  14. 14

    Stitziel, N. O. et al. J. Am. Coll. Cardiol. 69, 2054–2063 (2017).

  15. 15

    Khera, A. V. & Kathiresan, S. Nature Rev. Genet. 18, 331–344 (2017).

  16. 16

    Kazi, D. S. et al. J. Am. Med. Assoc. 316, 743–753 (2016).

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Correspondence to Sekar Kathiresan.

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Kathiresan, S. Putative medicines that mimic mutations. Nature 548, 530–531 (2017) doi:10.1038/nature23544

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