Is It Ever Wise to Edit Wild-Type Alleles? Engineered CRISPR Alleles Versus Millions of Years of Human Evolution.

Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 9505803 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4636 (Electronic) Linking ISSN: 10795642 NLM ISO Abbreviation: Arterioscler Thromb Vasc Biol Subsets: MEDLINE

Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
Original Publication: Dallas, TX : American Heart Association, c1995-

Proprotein Convertase 9*/genetics ; Proprotein Convertase 9*/metabolism ; Proprotein Convertases*/genetics ; Proprotein Convertases*/metabolism; Animals ; Humans ; Serine Endopeptidases/genetics ; Alleles ; Receptors, LDL/genetics

The tremendous burden of lipid metabolism diseases, coupled with recent developments in human somatic gene editing, has motivated researchers to propose population-wide somatic gene editing of PCSK9 (proprotein convertase subtilisin/kexin type 9) within the livers of otherwise healthy humans. The best-characterized molecular function of PCSK9 is its ability to regulate plasma LDL (low-density lipoprotein) levels through promoting LDL receptor degradation. Individuals with loss-of-function PCSK9 variants have lower levels of plasma LDL and reduced cardiovascular disease. Gain-of-function variants of PCSK9 are strongly associated with familial hypercholesterolemia. A new therapeutic strategy delivers CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats; CRISPR-associated protein 9) specifically to liver cells to edit the wild-type alleles of PCSK9 with the goal of producing a loss-of-function allele. This direct somatic gene editing approach is being pursued despite the availability of US Food and Drug Administration-approved PCSK9 inhibitors that lower plasma LDL levels. Here, we discuss other characterized functions of PCSK9 including its role in infection and host immunity. We explore important factors that may have contributed to the evolutionary selection of PCSK9 in several vertebrates, including humans. Until such time that more fully understand the multiple biological roles of PCSK9, the ethics of permanently editing the gene locus in healthy, wild-type populations remains highly questionable.
Competing Interests: Disclosures The authors are not aware of any conflicts of interests or biases that could be perceived as affecting the objectivity of this review

Science. 2022 Apr;376(6588):44-53. (PMID: 35357919)
Front Genet. 2020 Sep 23;11:1020. (PMID: 33173529)
FEBS J. 2020 Feb;287(3):515-528. (PMID: 31386798)
Endocr Rev. 2022 May 12;43(3):558-582. (PMID: 35552680)
Hum Gene Ther. 2014 Aug;25(8):740-6. (PMID: 24773182)
PLoS One. 2011;6(10):e26637. (PMID: 22039521)
J Clin Lipidol. 2022 Jul-Aug;16(4):483-490. (PMID: 35717446)
Am J Hum Genet. 2006 Sep;79(3):514-23. (PMID: 16909389)
Heart Views. 2019 Apr-Jun;20(2):74-75. (PMID: 31462965)
Diabetes Metab Syndr Obes. 2019 Oct 24;12:2221-2236. (PMID: 31695465)
Eur Heart J. 2014 Aug 21;35(32):2146-57. (PMID: 25053660)
N Engl J Med. 2006 Mar 23;354(12):1264-72. (PMID: 16554528)
J Am Heart Assoc. 2016 Apr 29;5(5):. (PMID: 27130349)
Nat Genet. 2003 Jun;34(2):154-6. (PMID: 12730697)
Arterioscler Thromb Vasc Biol. 2023 Jul;43(7):1081-1092. (PMID: 37259866)
Genetica. 2021 Feb;149(1):1-19. (PMID: 33515402)
Trends Biochem Sci. 2007 Feb;32(2):71-7. (PMID: 17215125)
Ann Parasitol. 2022;68(1):9-16. (PMID: 35436396)
JAMA Intern Med. 2016 Aug 1;176(8):1124-32. (PMID: 27379488)
J Lipid Res. 2022 Nov;63(11):100293. (PMID: 36209894)
Sci Transl Med. 2014 Oct 15;6(258):258ra143. (PMID: 25320235)
BMC Evol Biol. 2019 Jan 11;19(1):19. (PMID: 30634914)
Annu Rev Pharmacol Toxicol. 2017 Jan 6;57:223-244. (PMID: 27575716)
CMAJ. 2006 Apr 11;174(8):1124-9. (PMID: 16606962)
Metabolites. 2021 Apr 27;11(5):. (PMID: 33925362)
Curr Opin Lipidol. 2005 Aug;16(4):400-8. (PMID: 15990588)
Hepatol Commun. 2017 Nov;1(9):886-898. (PMID: 29130076)
BMJ Open. 2017 Sep 01;7(9):e016461. (PMID: 28864697)
Circ Cardiovasc Genet. 2017 Aug;10(4):e001632. (PMID: 28768753)
Adv Exp Med Biol. 2023;1396:139-156. (PMID: 36454465)
Glob Cardiol Sci Pract. 2013 Dec 30;2013(4):343-7. (PMID: 24749106)
Am J Clin Nutr. 2005 Feb;81(2):341-54. (PMID: 15699220)
J Intern Med. 2019 Nov;286(5):553-561. (PMID: 31166632)
J Immunol Res. 2020 Oct 14;2020:2687692. (PMID: 33123601)
Am J Prev Med. 2013 Sep;45(3):327-33. (PMID: 23953360)
Int J Mol Sci. 2020 May 30;21(11):. (PMID: 32486152)
World J Gastroenterol. 2016 Feb 14;22(6):1953-65. (PMID: 26877603)
ISRN Endocrinol. 2013 Jun 05;2013:341632. (PMID: 23862071)
J Diabetes Res. 2019 Nov 19;2019:5320156. (PMID: 31828161)
Arterioscler Thromb Vasc Biol. 2023 Jun;43(6):832-835. (PMID: 37128922)

R01 DK093399 United States DK NIDDK NIH HHS; R01 DK116079 United States DK NIDDK NIH HHS; R01 GM063904 United States GM NIGMS NIH HHS; R01 HL158054 United States HL NHLBI NIH HHS

Keywords: cardiovascular disease; ethics; gene editing; metabolic syndrome

EC 3.4.21.- (PCSK9 protein, human)
EC 3.4.21.- (Proprotein Convertase 9)
EC 3.4.21.- (Proprotein Convertases)
EC 3.4.21.- (Serine Endopeptidases)
0 (Receptors, LDL)

Date Created: 20231207 Date Completed: 20240126 Latest Revision: 20240320

20240320

PMC10948015

10.1161/ATVBAHA.123.318069

38059350