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FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice.
Blood Adv. 2021 05 11; 5(9):2385-2390.BA

Abstract

Sickle cell anemia (SCA) results from an abnormal sickle hemoglobin (HbS). HbS polymerizes upon deoxygenation, resulting in red blood cell (RBC) sickling and membrane damage that cause vaso-occlusions and hemolysis. Sickle RBCs contain less adenosine triphosphate and more 2,3-diphosphoglycerate than normal RBCs, which allosterically reduces hemoglobin (Hb) oxygen (O2) affinity (ie, increases the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen [P50]), potentiating HbS polymerization. Herein, we tested the effect of investigational agent FT-4202, an RBC pyruvate kinase (PKR) activator, on RBC sickling and membrane damage by administering it to Berkeley SCA mice. Two-week oral FT-4202 administration was well tolerated, decreasing HbS P50 to levels similar to HbA and demonstrating beneficial biological effects. In FT-4202-treated animals, there was reduced sickling in vivo, demonstrated by fewer irreversibly sickled cells, and improved RBC deformability, assessed at varying shear stress. Controlled deoxygenation followed by reoxygenation of RBCs obtained from the blood of FT-4202-treated mice showed a shift in the point of sickling to a lower partial pressure of oxygen (pO2). This led to a nearly 30% increase in RBC survival and a 1.7g/dL increase in Hb level in the FT-4202-treated SCA mice. Overall, our results in SCA mice suggest that FT-4202 might be a potentially useful oral antisickling agent that warrants investigation in patients with SCA.

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Authors+Show Affiliations

Shrestha A
Division of Experimental Hematology and Cancer Biology.
Chi M
Division of Experimental Hematology and Cancer Biology.
Wagner K
Division of Experimental Hematology and Cancer Biology.
Malik A
Division of Gastroenterology, Hepatology and Nutrition, and.
Korpik J
Erythrocyte Diagnostic Laboratory, Cancer and Blood Diseases Institute (CBDI), Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH.
Drake A
FORMA Therapeutics, Inc, Watertown, MA; and.
Fulzele K
FORMA Therapeutics, Inc, Watertown, MA; and.
Guichard S
FORMA Therapeutics, Inc, Watertown, MA; and.
Malik P
Division of Experimental Hematology and Cancer Biology. Division of Hematology, CBDI, CCHMC, Cincinnati, OH.

MeSH

Anemia, Sickle CellAnimalsAntisickling AgentsErythrocytes, AbnormalHemoglobin, SickleHumansMicePyruvate Kinase

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33944896

Citation

Shrestha, Archana, et al. "FT-4202, an Oral PKR Activator, Has Potent Antisickling Effects and Improves RBC Survival and Hb Levels in SCA Mice." Blood Advances, vol. 5, no. 9, 2021, pp. 2385-2390.
Shrestha A, Chi M, Wagner K, et al. FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice. Blood Adv. 2021;5(9):2385-2390.
Shrestha, A., Chi, M., Wagner, K., Malik, A., Korpik, J., Drake, A., Fulzele, K., Guichard, S., & Malik, P. (2021). FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice. Blood Advances, 5(9), 2385-2390. https://doi.org/10.1182/bloodadvances.2020003604
Shrestha A, et al. FT-4202, an Oral PKR Activator, Has Potent Antisickling Effects and Improves RBC Survival and Hb Levels in SCA Mice. Blood Adv. 2021 05 11;5(9):2385-2390. PubMed PMID: 33944896.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FT-4202, an oral PKR activator, has potent antisickling effects and improves RBC survival and Hb levels in SCA mice. AU - Shrestha,Archana, AU - Chi,Mengna, AU - Wagner,Kimberly, AU - Malik,Astha, AU - Korpik,Jennifer, AU - Drake,Adam, AU - Fulzele,Keertik, AU - Guichard,Sylvie, AU - Malik,Punam, PY - 2020/10/19/received PY - 2021/03/10/accepted PY - 2021/5/4/entrez PY - 2021/5/5/pubmed PY - 2021/6/1/medline SP - 2385 EP - 2390 JF - Blood advances JO - Blood Adv VL - 5 IS - 9 N2 - Sickle cell anemia (SCA) results from an abnormal sickle hemoglobin (HbS). HbS polymerizes upon deoxygenation, resulting in red blood cell (RBC) sickling and membrane damage that cause vaso-occlusions and hemolysis. Sickle RBCs contain less adenosine triphosphate and more 2,3-diphosphoglycerate than normal RBCs, which allosterically reduces hemoglobin (Hb) oxygen (O2) affinity (ie, increases the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen [P50]), potentiating HbS polymerization. Herein, we tested the effect of investigational agent FT-4202, an RBC pyruvate kinase (PKR) activator, on RBC sickling and membrane damage by administering it to Berkeley SCA mice. Two-week oral FT-4202 administration was well tolerated, decreasing HbS P50 to levels similar to HbA and demonstrating beneficial biological effects. In FT-4202-treated animals, there was reduced sickling in vivo, demonstrated by fewer irreversibly sickled cells, and improved RBC deformability, assessed at varying shear stress. Controlled deoxygenation followed by reoxygenation of RBCs obtained from the blood of FT-4202-treated mice showed a shift in the point of sickling to a lower partial pressure of oxygen (pO2). This led to a nearly 30% increase in RBC survival and a 1.7g/dL increase in Hb level in the FT-4202-treated SCA mice. Overall, our results in SCA mice suggest that FT-4202 might be a potentially useful oral antisickling agent that warrants investigation in patients with SCA. SN - 2473-9537 UR - https://www.unboundmedicine.com/medline/citation/33944896/FT_4202_an_oral_PKR_activator_has_potent_antisickling_effects_and_improves_RBC_survival_and_Hb_levels_in_SCA_mice_ DB - PRIME DP - Unbound Medicine ER -