EPELEUTON, A NOVEL SYNTHETIC SECOND GENERATION W-3 FATTY ACID, PROTECTS HUMANIZED SICKLE CELL MICE AGAINST HYPOXIA/REOXYGENATION ORGAN DAMAGE
Author(s): ,
Enrica Federti
Affiliations:
Dept of Medicine,University of Verona,Verona,Italie;Dept of Medicine,University of Verona,Verona,Italien;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italy;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italië;Dept of Medicine,University of Verona,Verona,Itália;Dept of Medicine,University of Veron
,
Alessandro Matte'
Affiliations:
Dept of Medicine,University of Verona,Verona,Italie;Dept of Medicine,University of Verona,Verona,Italien;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italy;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italië;Dept of Medicine,University of Verona,Verona,Itália;Dept of Medicine,University of Veron
,
Moayed Hamza
Affiliations:
Afimmune Ltd,Dublin,Irlande;Afimmune Ltd,Dublin,Irland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ireland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ierland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ирландия;Afimmune Ltd,Dublin,Irland
,
Adam Lafferty
Affiliations:
Afimmune Ltd,Dublin,Irlande;Afimmune Ltd,Dublin,Irland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ireland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ierland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ирландия;Afimmune Ltd,Dublin,Irland
,
David Coughlan
Affiliations:
Afimmune Ltd,Dublin,Irlande;Afimmune Ltd,Dublin,Irland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ireland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ierland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ирландия;Afimmune Ltd,Dublin,Irland
,
Markus Weissbach
Affiliations:
Afimmune Ltd,Dublin,Irlande;Afimmune Ltd,Dublin,Irland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ireland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ierland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ирландия;Afimmune Ltd,Dublin,Irland
,
Deepak L. Bhatt
Affiliations:
Brigham and Women's Hospital Heart & Vascular Center,Harvard Medical School,Boston,États-unis;Brigham and Women's Hospital Heart & Vascular Center,Harvard Medical School,Boston,Vereinigte Staaten;Brigham and Women's Hospital Heart & Vascular Center,Harvard Medical School,Boston,Stati Uniti;Brigham and Women's Hospital Heart & Vascular Center,Harvard Medical School,B
,
Veronica Riccardi
Affiliations:
Dept of Medicine,University of Verona,Verona,Italie;Dept of Medicine,University of Verona,Verona,Italien;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italy;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italië;Dept of Medicine,University of Verona,Verona,Itália;Dept of Medicine,University of Veron
,
Rachele Perissinotto
Affiliations:
Dept of Medicine,University of Verona,Verona,Italie;Dept of Medicine,University of Verona,Verona,Italien;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italy;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italië;Dept of Medicine,University of Verona,Verona,Itália;Dept of Medicine,University of Veron
,
Angela Siciliano
Affiliations:
Dept of Medicine,University of Verona,Verona,Italie;Dept of Medicine,University of Verona,Verona,Italien;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italy;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italië;Dept of Medicine,University of Verona,Verona,Itália;Dept of Medicine,University of Veron
,
John Climax
Affiliations:
Afimmune Ltd,Dublin,Irlande;Afimmune Ltd,Dublin,Irland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ireland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ierland;Afimmune Ltd,Dublin,Irlanda;Afimmune Ltd,Dublin,Ирландия;Afimmune Ltd,Dublin,Irland
,
Carlo Brugnara
Affiliations:
Dept of Laboratory Medicine,Harvard Medical School,Boston,États-unis;Dept of Laboratory Medicine,Harvard Medical School,Boston,Vereinigte Staaten;Dept of Laboratory Medicine,Harvard Medical School,Boston,Stati Uniti;Dept of Laboratory Medicine,Harvard Medical School,Boston,United States;Dept of Laboratory Medicine,Harvard Medical School,Boston,Estados Unidos;Dept of Laboratory Medicine,Harvard Med
Lucia De Franceschi
Affiliations:
Dept of Medicine,University of Verona,Verona,Italie;Dept of Medicine,University of Verona,Verona,Italien;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italy;Dept of Medicine,University of Verona,Verona,Italia;Dept of Medicine,University of Verona,Verona,Italië;Dept of Medicine,University of Verona,Verona,Itália;Dept of Medicine,University of Veron
(Abstract release date: 05/12/22) EHA Library. De Franceschi L. 06/10/22; 358340; P1483
Prof. Lucia De Franceschi
Prof. Lucia De Franceschi
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P1483

Type: Poster presentation

Session title: Sickle cell disease

Background
Sickle cell disease (SCD) is a hereditary red cell disorder with high mortality and morbidity. Although crizanlizumab, a P-selectin inhibitor, and voxelotor, an oral anti-sickling agent, have been recently approved for clinical management of SCD, therapeutic options to limit acute events and to reduce disease progression are still required. An attempt to target inflammatory vasculopathy and to modulate inflammatory response has been made based on evidence in other diseases such as in cardiovascular disease looking to administration of ω-3 fatty acids. In humanized SCD mice, we previously showed that polyunsaturated fatty acid supplementation protects against acute sickle cell-related lung and liver damages during hypoxia/reoxygenation (H/R) induced vaso-occlusive crisis (VOCs) (Kalish B et al. Haematologica 2016). This agrees with the observation that the resolution process actively controlled by specialized pro-resolving lipid mediators is defective in SCD (Matte A et al, Blood 2019).

Epeleuton (15-HEPE, 15 hydroxy eicosapentaenoic acid) is a novel synthetic second generation w-3 fatty acid which (i) has a favorable clinical safety profile, (ii) modulates systemic inflammation and triglyceride synthesis in patients with cardiometabolic disease (Climax J et al J Am Heart As 2020) and (ii) beneficially affects red cell indices in long-term studies in rats. 

Aims
To evaluate the impact of epeleuton on acute organ damage in a humanized mouse model of SCD. 

Methods
3-4 month old male and female mice healthy control (Hbatm1(HBA)Tow Hbbtm3(HBG1,HBB)Tow) and Tim Townes sickle mice (SCD, Hba tm1(HBA)Tow Hbb tm2(HBG1,HBB*)Tow) were used. Animals were treated for 6 weeks with epeleuton 1,000 mg/kg once daily or vehicle by gavage. Mice underwent 10 hours of hypoxia (8% oxygen), followed by 3 hours of reoxygenation (21% oxygen) to mimic acute VOCs (Matte A et al, Blood 2019). Hematologic parameters and molecular analysis of target organs for SCD such as lung were carried out. 

Results
In SCD mice exposed to H/R stress, we found that epeleuton (i) reduces H/R induced hemolysis; (ii) normalizes tyrosine-phosphorylation profile of red cell membrane proteins; and (iii) decreases neutrophil count. In lungs of SCD mice exposed to H/R stress, we observed that epeleuton prevents the H/R induced activation of inflammatory and redox related transcription factors NF-kB, p65 and Nrf2 local inflammatory response compared with vehicle-treated animals. Epeleuton treated SCD mice exposed to H/R stress showed down-regulation of VCAM-1 and E-selectin, markers of inflammatory vasculopathy as well as reduction of lung protein oxidation and expression of anti-oxidant systems such as heme-oxygenase-1 (HO-1) or peroxiredoxin-2. Similar changes were also observed in livers of epeleuton-treated SCD mice exposed to H/R stress compared with vehicle-treated SCD animals. Of note, epeleuton prevented the H/R induced up-regulation of both VCAM-1 and ICAM-1, suggesting a direct impact of treatment on vascular activation and inflammation.

Conclusion
In humanized SCD mice exposed to H/R stress to mimic acute VOCs, epeleuton acts as a multimodal agent targeting red cells, hemolysis, inflammatory response, and vascular dysfunction. Our data provide the rationale for epeleuton as a potential novel therapeutic option for clinical management of patients with SCD. 

Keyword(s): Mouse model, Sickle cell anemia, Vasoocclusive crisis

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P1483

Type: Poster presentation

Session title: Sickle cell disease

Background
Sickle cell disease (SCD) is a hereditary red cell disorder with high mortality and morbidity. Although crizanlizumab, a P-selectin inhibitor, and voxelotor, an oral anti-sickling agent, have been recently approved for clinical management of SCD, therapeutic options to limit acute events and to reduce disease progression are still required. An attempt to target inflammatory vasculopathy and to modulate inflammatory response has been made based on evidence in other diseases such as in cardiovascular disease looking to administration of ω-3 fatty acids. In humanized SCD mice, we previously showed that polyunsaturated fatty acid supplementation protects against acute sickle cell-related lung and liver damages during hypoxia/reoxygenation (H/R) induced vaso-occlusive crisis (VOCs) (Kalish B et al. Haematologica 2016). This agrees with the observation that the resolution process actively controlled by specialized pro-resolving lipid mediators is defective in SCD (Matte A et al, Blood 2019).

Epeleuton (15-HEPE, 15 hydroxy eicosapentaenoic acid) is a novel synthetic second generation w-3 fatty acid which (i) has a favorable clinical safety profile, (ii) modulates systemic inflammation and triglyceride synthesis in patients with cardiometabolic disease (Climax J et al J Am Heart As 2020) and (ii) beneficially affects red cell indices in long-term studies in rats. 

Aims
To evaluate the impact of epeleuton on acute organ damage in a humanized mouse model of SCD. 

Methods
3-4 month old male and female mice healthy control (Hbatm1(HBA)Tow Hbbtm3(HBG1,HBB)Tow) and Tim Townes sickle mice (SCD, Hba tm1(HBA)Tow Hbb tm2(HBG1,HBB*)Tow) were used. Animals were treated for 6 weeks with epeleuton 1,000 mg/kg once daily or vehicle by gavage. Mice underwent 10 hours of hypoxia (8% oxygen), followed by 3 hours of reoxygenation (21% oxygen) to mimic acute VOCs (Matte A et al, Blood 2019). Hematologic parameters and molecular analysis of target organs for SCD such as lung were carried out. 

Results
In SCD mice exposed to H/R stress, we found that epeleuton (i) reduces H/R induced hemolysis; (ii) normalizes tyrosine-phosphorylation profile of red cell membrane proteins; and (iii) decreases neutrophil count. In lungs of SCD mice exposed to H/R stress, we observed that epeleuton prevents the H/R induced activation of inflammatory and redox related transcription factors NF-kB, p65 and Nrf2 local inflammatory response compared with vehicle-treated animals. Epeleuton treated SCD mice exposed to H/R stress showed down-regulation of VCAM-1 and E-selectin, markers of inflammatory vasculopathy as well as reduction of lung protein oxidation and expression of anti-oxidant systems such as heme-oxygenase-1 (HO-1) or peroxiredoxin-2. Similar changes were also observed in livers of epeleuton-treated SCD mice exposed to H/R stress compared with vehicle-treated SCD animals. Of note, epeleuton prevented the H/R induced up-regulation of both VCAM-1 and ICAM-1, suggesting a direct impact of treatment on vascular activation and inflammation.

Conclusion
In humanized SCD mice exposed to H/R stress to mimic acute VOCs, epeleuton acts as a multimodal agent targeting red cells, hemolysis, inflammatory response, and vascular dysfunction. Our data provide the rationale for epeleuton as a potential novel therapeutic option for clinical management of patients with SCD. 

Keyword(s): Mouse model, Sickle cell anemia, Vasoocclusive crisis

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies