Session: 113. Sickle Cell Disease, Sickle Cell Trait, and Other Hemoglobinopathies, Excluding Thalassemias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Sickle Cell Disease, Translational Research, Animal model
Methods: In the hemin-induced renal fibrosis BSC model, 11-week-old BSC mice were injected with either vehicle or hemin (7 µmoles/kg body weight; 5 times on alternate days) and monitored for 25 weeks. Hemin-injected mice received control or mitapivat (1200 ppm) chow at the time of the first injection and throughout the study. We assessed histologic parameters via hematoxylin and eosin, Prussian blue, and Masson’s trichrome staining at the end of the study.
To further evaluate glomerular damage, the anti-GBM nephritis model was studied. Ten-week-old 129/SvJ mice were pre-sensitized with 50 mL of 1.5 mg/mL sheep IgG, administered intraperitoneally in complete Freund’s adjuvant. Five days later, the mice were injected with 25 mL sheep anti-GBM serum to induce nephritis, and were given vehicle or tebapivat (10 mg/kg) orally for 10 days on the same day of nephritis induction. Therapeutic benefits were evaluated on Day 10 through histologic and proteomic analysis of kidney tissues.
Results: Histologic analysis in the hemin-induced BSC mouse model showed that mice administered control chow and hemin experienced a significant increase in the occurrence and severity of chronic nephropathy, iron deposition, and kidney fibrosis, compared with the mitapivat-treated group. Mitapivat-treated mice showed a notable reduction in iron deposition in the inner medulla (staining score: 1.70±0.21 vs. 0.75±0.25, p=0.014) and fibrosis score (1.17±0.26 vs. 0.17±0.17, p=0.002). Reduced protein casts, mononuclear interstitial inflammation, and medullary congestion were noted in the kidneys of mice treated with mitapivat compared with hemin-controls.
In the anti-GBM nephritis model, tebapivat treatment increased kidney PKM2 activity by 5-fold compared with no change in the vehicle-treated mice. Tebapivat treatment reduced the percentage of glomeruli with crescents compared with vehicle-treated mice (1.0%±0.3 vs. 10.0%±2.4, p<0.002), with no impact on proteinuria; likely due to the short study duration of 10 days. Proteomics evaluation of kidney tissue comparing tebapivat with vehicle groups indicated that tebapivat downregulated several extracellular matrix proteins, including multiple collagens (Col1a1, Col1a2, Col3a1, Col5a2, Col6a6) and elastin. Tebapivat treatment downregulated α-smooth muscle actin, a marker for myofibroblast activation, suggesting that PK activation may modulate myofibroblast function in kidney disease.
Conclusions: Our studies demonstrated that PK activation reduced the effects of hemin-induced renal fibrosis in a SCD mouse model and also reduced crescent formation in the context of anti-GBM nephritis. These findings underscore the potential of PK activators in improving kidney health by reducing hemolysis and vaso-occlusion via PKR activation and slowing fibrosis development via PKM2 activation. Further studies to explore the potential role of PK activators in SCN are ongoing, including a phase 2 study to assess the efficacy and safety of mitapivat in pts with SCD and nephropathy (NCT06286046), and RISE UP, a phase 2/3 study to evaluate the safety and efficacy of mitapivat in pts with SCD (NCT05031780).
Disclosures: Nguyen: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Ingersoll: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Lizotte: Agios Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other: Employee at the time of research. Chen: Agios Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other: Employee at the time of research. Tsai: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Wind-Rotolo: Agios: Current Employment, Current equity holder in publicly-traded company. Gao: Agios Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company.