Rapamycin increases fetal hemoglobin and ameliorates the nociception phenotype in sickle cell mice

Fetal hemoglobin-inducing therapies are disease-modifying and ameliorate the pain phenotype in sickle cell disease (SCD). Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, increases HbF in erythroid precursor cells in vitro. We hypothesized that rapamycin would increase HbF levels and improve nociception phenotype in SCD mice. We used sine-wave electrical stimulation to examine nocifensive phenotype and evaluate myelinated [2000 Hz (Aβ-fiber) and 250 Hz (Aδ-fiber)] and unmyelinated (5 Hz C-fibers)] sensory fiber function. Rapamycin significantly increased γ-globin mRNA and HbF levels [+ 2.3% (0.7, 3.9), mean increase (95% confidence interval, CI), p = 0.006]. In homozygous (sickling) mice, long- (16 weeks), but not short-term (6 weeks), rapamycin treatment increased 2000 Hz and 250 Hz current thresholds in a pattern that varied according to sex. In male, but not female mice, rapamycin (compared with vehicle) was associated with increases in 2000 Hz [21 Units (7, 35), mean difference (95% CI), p = 0.009 for sex ∗ treatment interaction] and 250 Hz [9 Units (1, 16), p = 0.01] current thresholds. In rapamycin-treated homozygotes, HbF levels directly correlated with myelinated [2000 Hz(Aβ-fiber, r = 0.58, p = 0.01) and 250 Hz(Aδ-fiber, r = 0.6, p = 0.01)] but not unmyelinated sensory fiber current thresholds. These findings suggest that in SCD mice, rapamycin increases HbF and modulates current thresholds of myelinated fibers. Therefore, mTOR signaling might be implicated in the pathobiology of SCD.