medigraphic.com
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

2018, Number 5

<< Back

Rev Invest Clin 2018; 70 (5)

New Biotechnological Treatments for Lipid Disorders

Valencia-Enciso N, Mendivil CO

Language: English
References: 80
Page: 244-254
PDF size: 111.88 Kb.


ABSTRACT

Disorders of lipid and lipoprotein metabolism play a central role in the pathogenesis of atherosclerotic cardiovascular diseases (CVDs). Despite the widespread use of efficacious lipid-modifying therapies, the residual risk of CVD remains unacceptably high. The purpose of this manuscript is to review the application of new technologies in the treatment of lipid disorders. New therapies work mostly at the gene expression level and are, therefore, different from traditional small-molecule drugs that work mainly by inhibiting already synthesized proteins. We will briefly lay out the function of the gene products targeted by the new agents. Then, we will organize our review of new biotechnological treatments by the molecular approach, namely: monoclonal antibodies, antisense oligonucleotides, small-interfering RNAs, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated 9 (Cas9)-based genome editing. The paper concludes with the description of the current clinical studies and the perspectives for the use of these agents.


REFERENCES

  1. Bruzzone G, Corbelli G, Belci P, et al. Cholesterol lowering therapy: treat to target or reduce the global risk? The unresolved problem of residual risk. Curr Pharm Des. 2016;22:5676-86.

  2. Turner RM, Yin P, Hanson A, et al. Investigating the prevalence, predictors, and prognosis of suboptimal statin use early after a non-ST elevation acute coronary syndrome. J Clin Lipidol. 2017; 11:204-14.

  3. Ajufo E, Rader DJ. New therapeutic approaches for familial hypercholesterolemia. Annu Rev Med. 2018;69:113-31.

  4. Chait A, Eckel RH. Lipids, lipoproteins, and cardiovascular disease: clinical pharmacology now and in the future. J Clin Endocrinol Metab. 2016;101:804-14.

  5. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003; 34:154-6.

  6. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100:928-33.

  7. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A. 2004;101:7100-5.

  8. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161-5.

  9. Cohen JC, Boerwinkle E, Mosley TH Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-72.

  10. Kathiresan S, Myocardial Infarction Genetics Consortium. A PCSK9 missense variant associated with a reduced risk of earlyonset myocardial infarction. N Engl J Med. 2008;358:2299-300.

  11. Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factorlike repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007; 282:18602-12.

  12. Mattijssen F, Kersten S. Regulation of triglyceride metabolism by angiopoietin-like proteins. Biochim Biophys Acta. 2012;1821: 782-9.

  13. Koishi R, Ando Y, Ono M, et al. Angptl3 regulates lipid metabolism in mice. Nat Genet. 2002;30:151-7.

  14. Haller JF, Mintah IJ, Shihanian LM, et al. ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. J Lipid Res. 2017;58:1166-73.

  15. Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69:2054-63.

  16. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377:211-21.

  17. Robciuc MR, Maranghi M, Lahikainen A, et al. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013;33:1706-13.

  18. Mendivil CO, Zheng C, Furtado J, et al. Metabolism of very-lowdensity lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins. Arterioscler Thromb Vasc Biol. 2010;30:239-45.

  19. Mendivil CO, Rimm EB, Furtado J, Sacks FM. Apolipoprotein E in VLDL and LDL with apolipoprotein C-III is associated with a lower risk of coronary heart disease. J Am Heart Assoc. 2013; 2:e000130.

  20. Mendivil CO, Rimm EB, Furtado J, Chiuve SE, Sacks FM. Lowdensity lipoproteins containing apolipoprotein C-III and the risk of coronary heart disease. Circulation. 2011;124:2065-72.

  21. Jensen MK, Rimm EB, Furtado JD, Sacks FM. Apolipoprotein C-III as a potential modulator of the association between HDL-cholesterol and incident coronary heart disease. J Am Heart Assoc. 2012;1:jah3-e000232.

  22. Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322:1702-5.

  23. Maranhão RC, Carvalho PO, Strunz CC, Pileggi F. Lipoprotein (a): structure, pathophysiology and clinical implications. Arq Bras Cardiol. 2014;103:76-84.

  24. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412-23.

  25. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518-28.

  26. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495-7.

  27. Stoekenbroek RM, Kastelein JJ, Huijgen R. PCSK9 inhibition: the way forward in the treatment of dyslipidemia. BMC Med. 2015; 13:258.

  28. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebocontrolled trial. Lancet. 2015;385:331-40.

  29. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA part B): A randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341-50.

  30. Raal FJ, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017;5:280-90.

  31. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531-40.

  32. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate-or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia. JAMA. 2014;311:1870.

  33. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809-19.

  34. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016;315:1580-90.

  35. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-9.

  36. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-22.

  37. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017;377:633-43.

  38. Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996-3003.

  39. Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J. 2016;37:3588-95.

  40. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J. 2015;169:906-15E+15.

  41. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: The ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186-94.

  42. Bays H, Gaudet D, Weiss R, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab. 2015;100:3140-8.

  43. Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9:758-69.

  44. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489-99.

  45. Steg P, The ODYSSEY OUTCOMES investigators. Presented at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL; 2018. Available from: (accessed August 23, 2018)

  46. Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527-39.

  47. Beyer TP, Eacho PI, Schroeder KM, et al. A PCSK9 antibody that blocks binding to LDLR while allowing normal PCSK9 inactivation by furin is afforded a reduced clearance rate and a longer duration of effect in mice. Atheroscler Thromb Vasc Biol. 2015; 35:A538.

  48. Kastelein JJ, Nissen SE, Rader DJ, et al. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled phase 2 study. Eur Heart J. 2016;37:1360-9.

  49. Gusarova V, Alexa CA, Wang Y, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res. 2015;56:1308-17.

  50. Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med. 2017; 377:296-7.

  51. Miller CM, Harris EN. Antisense oligonucleotides: treatment strategies and cellular internalization. RNA Dis. 2016;3:e1393.

  52. Toth PP. Antisense therapy and emerging applications for the management of dyslipidemia. J Clin Lipidol. 2011;5:441-9.

  53. Crooke ST. Molecular mechanisms of antisense oligonucleotides. Nucleic Acid Ther. 2017;27:70-7.

  54. Besseling J, Hovingh GK, Stroes ES. Antisense oligonucleotides in the treatment of lipid disorders: pitfalls and promises. Neth J Med. 2013;71:118-22.

  55. Kurreck J. Antisense technologies. Improvement through novel chemical modifications. Eur J Biochem. 2003;270:1628-44.

  56. Agrawal S, Jiang Z, Zhao Q, et al. Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: in vitro and in vivo studies. Proc Natl Acad Sci U S A. 1997;94:2620-5.

  57. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:998-1006.

  58. Stein EA, Dufour R, Gagne C, et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebocontrolled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012; 126:2283-92.

  59. Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J. 2015;36:566-75.

  60. Duell PB, Santos RD, Kirwan BA, et al. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol. 2016;10:1011-21.

  61. Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med. 2017;377:222-32.

  62. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373:438-47.

  63. Digenio A, Dunbar RL, Alexander VJ, et al. Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes. Diabetes Care. 2016;39:1408-15.

  64. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014; 371:2200-6.

  65. Graham MJ, Viney N, Crooke RM, Tsimikas S. Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans. J Lipid Res. 2016;57:340-51.

  66. Tsimikas S, Viney NJ, Hughes SG, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebocontrolled phase 1 study. Lancet. 2015;386:1472-83.

  67. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388:2239-53.

  68. Ozcan G, Ozpolat B, Coleman RL, Sood AK, Lopez-Berestein G. Preclinical and clinical development of siRNA-based therapeutics. Adv Drug Deliv Rev. 2015;87:108-19.

  69. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136:642-55.

  70. Kim DH, Rossi JJ. Strategies for silencing human disease using RNA interference. Nat Rev Genet. 2007;8:173-84.

  71. Khvorova A. Oligonucleotide therapeutics - A new class of cholesterol- lowering drugs. N Engl J Med. 2017;376:4-7.

  72. Juliano R, Alam MR, Dixit V, Kang H. Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Res. 2008;36:4158-71.

  73. Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med. 2017;376:41-51.

  74. Mali P, Yang L, Esvelt KM, et al. RNA-guided human genome engineering via cas9. Science. 2013;339:823-6.

  75. Musunuru K. Genome editing: the recent history and perspective in cardiovascular diseases. J Am Coll Cardiol. 2017;70:2808-21.

  76. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339:819-23.

  77. Gilbert LA, Larson MH, Morsut L, et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell. 2013;154:442-51.

  78. Ran FA, Cong L, Yan WX, et al. In vivo genome editing using Staphylococcus aureus cas9. Nature. 2015;520:186-91.

  79. Chadwick AC, Wang X, Musunuru K. In vivo base editing of PCSK9 (Proprotein convertase subtilisin/Kexin Type 9) as a therapeutic alternative to genome editing. Arterioscler Thromb Vasc Biol. 2017;37:1741-7.

  80. Chadwick AC, Evitt NH, Lv W, Musunuru K. Reduced blood lipid levels with in vivo CRISPR-cas9 base editing of ANGPTL3. Circulation. 2018;137:975-7.




2020     |     www.medigraphic.com