Introduction: Sickle cell disease (SCD) is a hemolytic anemia caused by a mutation in the β-globin gene. Recurrent vaso-occlusive crisis (VOC) induces acute and chronic pain and leads to irreversible organ failure. While the Townes HbSS mouse model of SCD is well characterized for evaluating anemia and hemolysis, progression of organ dysfunction during aging is less documented. IMA001, a nucleotide from the NAD+ pathway, has been shown to improve anemia and VOCs in HbSS mice. This study aimed to characterize organ function in HbSS mice during aging and to evaluate the effect of IMA001.

Experimental design: HbSS mice aged 7-9 months were treated for 8 weeks via drinking water with either IMA001 (1000 mg/kg) or vehicle (water); age-matched C57BL/6J (C57) mice were treated with vehicle. Cardiac geometry and function were assessed by echocardiography and kidney function by glomerular filtration rate (GFR). Blood, urine and organs were collected for biochemical, histopathological (H&E) and metabolite (HPLC-MS/MS) analyses.

Results: Administration of IMA001 for 8 weeks was well tolerated.Metabolite profiling revealed efficient exposure to IMA001.

Cardiac geometry and function were evaluated at baseline (W0) and after 8-week treatment (W8). At W0, HbSS mice showed left ventricle (LV) dilation with significantly higher volumes compared to C57 mice [diastole (d): +36%, p<0.05; systole (s): +30%, p<0.05]. LV hypertrophy was observed in both diastole and systole with thicker anterior wall (d: +18%, p<0.0001; s: +20%, p<0.0001) and posterior wall (d: +32%, p<0.0001; s: +32%, p<0.0001). In HbSS mice, hypertrophy was stable over time, whereas dilation further progressed at W8, with larger volumes (d: +13%, p<0.05; s: +43%, p<0.01 vs. W0, and d: +59% p<0.0001; s: +89% p<0.0001 vs. C57) and increased systolic diameter (+23%, p<0.01).

Systolic function of HbSS mice was normal at W0 but altered at W8, as shown by reduced ejection fraction (–17% p<0.05 vs. W0, and –15% p<0.05 vs. C57) and fractional shortening (–28% p<0.01 vs. W0, and –26% p<0.0001 vs. C57). Compared to C57, HbSS mice also exhibited diastolic dysfunction. Despite comparable E/A ratio in C57 and HbSS mice at W0, the E‘/A’ ratio was significantly lower in HbSS mice (–37%, p<0.0001), indicating impaired LV relaxation that further declined at W8 (–46%, p<0.001). HbSS mice also showed increased isovolumic relaxation time (IVRT) at W8 (+18%, p<0.05 vs. W0; +30%, p<0.001 vs. C57), indicating a relaxation default. This was associated with a rising trend in E/E’ ratio in HbSS vs. C57 (+23%, p=0.058), suggesting higher filling pressure and thus poor diagnosis.

Treatment with IMA001 did not prevent cardiac remodeling nor the systolic function decline seen in vehicle-treated HbSS mice. While no significant effect was observed on E/A, E/E' ratio and IVRT, IMA001 treatment achieved a protective effect by increasing E'/A’ up to 1 (+40% p<0.0001 vs. vehicle), suggesting alleviation of the relaxation default.

Liver injury markers, including aspartate aminotransferase, alanine aminotransferase and bilirubin, were elevated in HbSS mice vs. C57 (fold change: 1.5, p<0.05; 2.9, p<0.001; 19.0, p<0.001, respectively), with no improvement after IMA001 treatment. GFR was similar across groups. The albumin/creatinine ratio was higher in HbSS mice (+38%, p<0.05) and urinary KIM-1 excretion rose (+169%, p<0.05) without improvement with IMA001.

Histological analysis confirmed multiorgan (heart, liver, spleen, lungs, kidneys and bone marrow) damage in older HbSS vs. C57 mice. IMA001 treatment appeared to slightly reduce tissue lesion incidence, particularly in the liver (severe lesions observed in 40% vehicle vs. 20% IMA001) and heart (mild lesions observed in 30% vehicle vs. 20% IMA001).

Conclusion:This study characterizes organ damage in 7-9-month-old HbSS mice and documents its further progression over an 8-week experimental period. HbSS mice displayed progressive cardiac remodeling and dysfunction and modest renal and hepatic impairments. Administration of IMA001 for 8 weeks was well tolerated and demonstrated potential cardioprotective effects through improving diastolic function, as well as a reduction in liver lesion incidence. Our study shows that in addition to the beneficial effect on anemia and hemolysis, IMA001 could be an effective therapeutic option to moderate organ damage associated with SCD.

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2025
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