ChemicalBook CAS DataBase List 915430-78-3

915430-78-3

Name	NA
CAS	915430-78-3

Chemical Properties

form	Solid
color	White to off-white
Sequence	DNA, d(P-thio)([2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]rG-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-m5C-T-T-G-T-m5C-m5C-A-G-m5C-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]m5rU)

Hazard Information

Uses

Volanesorsen (ISIS 304801) is an antisense oligonucleotide inhibitor of apolipoprotein CIII (apo-CIII) mRNA that reduces triglyceride levels and improves insulin resistance. Volanesorsen is being studied in the treatment of hypertriglyceridemia, familial chylosiderosis syndrome, and type 2 diabetes[1][2][3][4][5].

in vivo

Volanesorsen (1.5-50 mg/kg; i.p.; once a week for 2 weeks) dose-dependently reduces human apolipoprotein CIII (apo-CIII) mRNA, plasma apo-CIII protein and triglyceride (TG) levels in human apo-CIII transgenic mice^[1]. Volanesorsen (4-40 mg/kg; s.c.; once a week for 13 weeks) dose-responsively reduces apoC-III mRNA levels in the liver of cynomolgus monkeys^[1]. Volanesorsen (10 mg/kg; s.c.; once weekly for 10 weeks) reduces plasma triglyceride levels in hypertriglyceridemic rhesus monkeys^[1].

Animal Model:	Chow-Fed Cynomolgus^[1]
Dosage:	4, 8, 12 and 40 mg/kg
Administration:	Subcutaneous injection (s.c.) Once a week for 13 weeks
Result:	Reduced apoC-III mRNA by 47%, 51%, 80%, and 89% in a dose-responsive manner.

Animal Model:	Rhesus monkeys with hypertriglyceridemia after taking high fructose supplements^[1]
Dosage:	10 mg/kg
Administration:	Subcutaneous injection (s.c.) Once a week for 10 weeks
Result:	Reduced plasma triglycerides, very low–density lipoprotein (VLDL)+chylomicron triglyceride, and decreased postprandial triglyceride excursion, while increasing high-density lipoprotein-cholesterol (HDL-C) in hypertriglyceridemic rhesus monkeys.

IC 50

apoC3

References

[1] Graham MJ, Lee RG, Bell TA 3rd, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.?Circ Res. 2013;112(11):1479-1490. DOI:10.1161/CIRCRESAHA.111.300367
[2] Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome.?N Engl J Med. 2014;371(23):2200-2206. DOI:10.1056/NEJMoa1400284
[3] Post N, Yu R, Greenlee S, et al. Metabolism and Disposition of Volanesorsen, a 2'-O-(2 methoxyethyl) Antisense Oligonucleotide, Across Species. Drug Metab Dispos. 2019;47(10):1164-1173. DOI:10.1124/dmd.119.087395
[4] Lightbourne M, et al. Volanesorsen, an Antisense Oligonucleotide to Apolipoprotein-CIII, Decreases Triglycerides and Increases Lipoprotein Lipase Activity in Partial Lipodystrophy[J]. Journal of the Endocrine Society, 2021, 5(Supplement_1): A305-A305. DOI:10.1016/j.jacl.2022.06.011
[5] Paik J, et al. Volanesorsen: first global approval[J]. Drugs, 2019, 79(12): 1349-1354. DOI:10.1007/s40265-019-01168-z

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