High density lipoprotein future or investigational therapies: Difference between revisions
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This methods aim at directly increasing the serum levels of HDL through the infusion of reconstituted and recombinant preparations of HDLs (rHDLs). Recombinant HDLs are made from apo A-1 derived from cellular expression systems while recombinant HDLs are apo A-1 derived from human. Both preparations have been complexed with [[phospholipids]]. The reconstituted forms are relatively cheaper and easier to produce. | This methods aim at directly increasing the serum levels of HDL through the infusion of reconstituted and recombinant preparations of HDLs (rHDLs). Recombinant HDLs are made from apo A-1 derived from cellular expression systems while recombinant HDLs are apo A-1 derived from human. Both preparations have been complexed with [[phospholipids]]. The reconstituted forms are relatively cheaper and easier to produce. | ||
====ApoA-1 Milano==== | ====ApoA-1 Milano==== | ||
Some individuals in rural Italy were identified with a genetic variant of apo A-1 which conferred some protection against atherosclerosis despite the presence of very low HDL levels (10-30 mg/dl), elevated plasma LDL, and moderate hypertriglyceridemia.<ref name="Sirtori-2001">{{Cite journal | last1 = Sirtori | first1 = CR. | last2 = Calabresi | first2 = L. | last3 = Franceschini | first3 = G. | last4 = Baldassarre | first4 = D. | last5 = Amato | first5 = M. | last6 = Johansson | first6 = J. | last7 = Salvetti | first7 = M. | last8 = Monteduro | first8 = C. | last9 = Zulli | first9 = R. | title = Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. | journal = Circulation | volume = 103 | issue = 15 | pages = 1949-54 | month = Apr | year = 2001 | doi = | PMID = 11306522 }}</ref> Studies indicated that intravenous infusion recombinant apoA-I Milano (ETC-216) promotes regression of atherosclerosis lesion to a greater extent than wild type apoA-I as measured by intravascular ultrasound within 5 weeks of treatment.<ref name="Nissen-2003">{{Cite journal | last1 = Nissen | first1 = SE. | last2 = Tsunoda | first2 = T. | last3 = Tuzcu | first3 = EM. | last4 = Schoenhagen | first4 = P. | last5 = Cooper | first5 = CJ. | last6 = Yasin | first6 = M. | last7 = Eaton | first7 = GM. | last8 = Lauer | first8 = MA. | last9 = Sheldon | first9 = WS. | title = Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. | journal = JAMA | volume = 290 | issue = 17 | pages = 2292-300 | month = Nov | year = 2003 | doi = 10.1001/jama.290.17.2292 | PMID = 14600188 }}</ref> However, further studies regarding these agents have been halted by procedural and manufacturing difficulties. | Some individuals in rural Italy were identified with a genetic variant of apo A-1 which conferred some protection against atherosclerosis despite the presence of very low HDL levels (10-30 mg/dl), elevated plasma LDL, and moderate hypertriglyceridemia.<ref name="Sirtori-2001">{{Cite journal | last1 = Sirtori | first1 = CR. | last2 = Calabresi | first2 = L. | last3 = Franceschini | first3 = G. | last4 = Baldassarre | first4 = D. | last5 = Amato | first5 = M. | last6 = Johansson | first6 = J. | last7 = Salvetti | first7 = M. | last8 = Monteduro | first8 = C. | last9 = Zulli | first9 = R. | title = Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. | journal = Circulation | volume = 103 | issue = 15 | pages = 1949-54 | month = Apr | year = 2001 | doi = | PMID = 11306522 }}</ref> Studies indicated that intravenous infusion of recombinant apoA-I Milano (ETC-216) promotes regression of atherosclerosis lesion to a greater extent than wild type apoA-I as measured by intravascular ultrasound within 5 weeks of treatment.<ref name="Nissen-2003">{{Cite journal | last1 = Nissen | first1 = SE. | last2 = Tsunoda | first2 = T. | last3 = Tuzcu | first3 = EM. | last4 = Schoenhagen | first4 = P. | last5 = Cooper | first5 = CJ. | last6 = Yasin | first6 = M. | last7 = Eaton | first7 = GM. | last8 = Lauer | first8 = MA. | last9 = Sheldon | first9 = WS. | title = Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. | journal = JAMA | volume = 290 | issue = 17 | pages = 2292-300 | month = Nov | year = 2003 | doi = 10.1001/jama.290.17.2292 | PMID = 14600188 }}</ref> However, further studies regarding these agents have been halted by procedural and manufacturing difficulties. | ||
====CSL-112==== | ====CSL-112==== | ||
CSL-112 (CSL Behring), a reformulated version of CSL-111, is a reconstituted HDL complexed with soybean phosphatidylcholine, and has been reported to cause up to 20-fold elevation in serum pre-Beta-1-HDL following a single infusion according to phase 1 trial.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title =http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url =http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> Currently, there are pending results regarding phase 2a which was recently completed. CSL-111 [[ERASE trial]] which examined the regression of coronary atherosclerotic lesions in ACS patients was discontinued due to abnormal liver transaminase elevations observed with the high dose. However, there was no significant change in atheroma volume (measured by IVUS) despite a 64% increase in HDL and a 23% reduction in LDL.<ref name="pmid17387133">{{cite journal |author=Tardif JC, Grégoire J, L'Allier PL, ''et al.'' |title=Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=297|issue=15 |pages=1675–82 |year=2007 |month=April |pmid=17387133 |doi=10.1001/jama.297.15.jpc70004 |url=}}</ref> | CSL-112 (CSL Behring), a reformulated version of CSL-111, is a reconstituted HDL complexed with soybean phosphatidylcholine, and has been reported to cause up to 20-fold elevation in serum pre-Beta-1-HDL following a single infusion according to phase 1 trial.<ref name="circ.ahajournals.org">{{Cite web | last = | first = | title =http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | url =http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851 | publisher = | date = | accessdate = 16 September 2013 }}</ref> Currently, there are pending results regarding phase 2a which was recently completed. CSL-111 [[ERASE trial]] which examined the regression of coronary atherosclerotic lesions in ACS patients was discontinued due to abnormal liver transaminase elevations observed with the high dose. However, there was no significant change in atheroma volume (measured by IVUS) despite a 64% increase in HDL and a 23% reduction in LDL.<ref name="pmid17387133">{{cite journal |author=Tardif JC, Grégoire J, L'Allier PL, ''et al.'' |title=Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=297|issue=15 |pages=1675–82 |year=2007 |month=April |pmid=17387133 |doi=10.1001/jama.297.15.jpc70004 |url=}}</ref> | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
The association between HDL level and cardiovascular disease has been widely reported in the literature. In fact, 1 out of every 7 statin treated patients has residual cardiovascular disease,[1] which sheds light to the importance of developing new therapies targeting HDL quantity and quality in high risk patients.[2]
The Need
The importance of increasing serum levels and functionality of HDL-C in lowering residual cardiovascular risks in patients with acute coronary syndromes cannot be over-emphasized. First of all, some recent studies reported failures of orally active medications that increase serum levels of HDL-C to potentially improve cardiovascular outcomes, such as niacin in the AIM-HIGH Trial. This have shifted the focus of researchers to other targets of HDL therapy aimed at increasing the serum levels of HDL as well as its functionality i.e., cellular cholesterol efflux and HDL-mediated reverse cholesterol transport mechanisms. Secondly, since the available oral medications elevate HDL over weeks to months, there is the need for medications which rapidly improve outcomes during acute vascular events.
Direct Infusion of Apo A-1
This methods aim at directly increasing the serum levels of HDL through the infusion of reconstituted and recombinant preparations of HDLs (rHDLs). Recombinant HDLs are made from apo A-1 derived from cellular expression systems while recombinant HDLs are apo A-1 derived from human. Both preparations have been complexed with phospholipids. The reconstituted forms are relatively cheaper and easier to produce.
ApoA-1 Milano
Some individuals in rural Italy were identified with a genetic variant of apo A-1 which conferred some protection against atherosclerosis despite the presence of very low HDL levels (10-30 mg/dl), elevated plasma LDL, and moderate hypertriglyceridemia.[3] Studies indicated that intravenous infusion of recombinant apoA-I Milano (ETC-216) promotes regression of atherosclerosis lesion to a greater extent than wild type apoA-I as measured by intravascular ultrasound within 5 weeks of treatment.[4] However, further studies regarding these agents have been halted by procedural and manufacturing difficulties.
CSL-112
CSL-112 (CSL Behring), a reformulated version of CSL-111, is a reconstituted HDL complexed with soybean phosphatidylcholine, and has been reported to cause up to 20-fold elevation in serum pre-Beta-1-HDL following a single infusion according to phase 1 trial.[5] Currently, there are pending results regarding phase 2a which was recently completed. CSL-111 ERASE trial which examined the regression of coronary atherosclerotic lesions in ACS patients was discontinued due to abnormal liver transaminase elevations observed with the high dose. However, there was no significant change in atheroma volume (measured by IVUS) despite a 64% increase in HDL and a 23% reduction in LDL.[6]
CER-001
Cholesterol Ester Transfer Protein (CETP) Inhibition
CETi-1 Vaccine
JTT-705
De-lipidated HDL Infusions
HDL Mimetics
ApoA-1 Mimetic Peptides
- D-4F and L-4F
ATI-5261 Synthetic Peptide
Endothelial Lipase Inhibitors
LCAT Modulators
Endocannabinoid Receptor Blockers
ApoA-1 Upregulators
RVX-208
Synthetic Liver X Receptor (LXR) Agonists
Synthetic FXR Agonists
Gene Therapy
References
- ↑ Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C; et al. (2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins". Lancet. 366 (9493): 1267–78. doi:10.1016/S0140-6736(05)67394-1. PMID 16214597. Review in: ACP J Club. 2006 May-Jun;144(3):62
- ↑ Mora S, Glynn RJ, Ridker PM (2013). "High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy". Circulation. 128 (11): 1189–97. doi:10.1161/CIRCULATIONAHA.113.002671. PMID 24002795.
- ↑ Sirtori, CR.; Calabresi, L.; Franceschini, G.; Baldassarre, D.; Amato, M.; Johansson, J.; Salvetti, M.; Monteduro, C.; Zulli, R. (2001). "Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study". Circulation. 103 (15): 1949–54. PMID 11306522. Unknown parameter
|month=ignored (help) - ↑ Nissen, SE.; Tsunoda, T.; Tuzcu, EM.; Schoenhagen, P.; Cooper, CJ.; Yasin, M.; Eaton, GM.; Lauer, MA.; Sheldon, WS. (2003). "Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial". JAMA. 290 (17): 2292–300. doi:10.1001/jama.290.17.2292. PMID 14600188. Unknown parameter
|month=ignored (help) - ↑ "http://circ.ahajournals.org/cgi/content/meeting_abstract/126/21_MeetingAbstracts/A11851". Retrieved 16 September 2013. External link in
|title=(help) - ↑ Tardif JC, Grégoire J, L'Allier PL; et al. (2007). "Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial". JAMA : the Journal of the American Medical Association. 297 (15): 1675–82. doi:10.1001/jama.297.15.jpc70004. PMID 17387133. Unknown parameter
|month=ignored (help)