Improved Fetal Hemoglobin With mTOR Inhibitor–Based Immunosuppression in a Kidney Transplant Recipient With Sickle Cell Disease

Gaudré, N.; Cougoul, P.; Bartolucci, Pablo; Dörr, Gaëlle; Bura-Rivière, A.; Kamar, Nassim; Bello, Arnaud Del

doi:10.1111/ajt.14263

Cited by 29 publications

(27 citation statements)

References 17 publications

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“…To the best of our knowledge, this is the first report documenting an increase in HbF after treatment with sirolimus in patients with SCD. The only other report showing a similar effect was in a patient receiving everolimus, another mTOR inhibitor (Gaudre et al , ). This may indicate that the increase in HbF is a class effect rather than agent‐specific.…”

Section: Haematological Data Of the Patients At Baseline And After Trmentioning

confidence: 76%

“…While most patients tolerate and respond to HC, others do not, and the search for other agents to raise HbF is on‐going. Mechanistic/mammalian target of Rapamycin (mTOR) inhibitors were reported to increase HBG1/HBG2 mRNA (Fibach et al , ) and HbF production in human cell cultures (Pecoraro et al , ), an animal model of SCD (Khaibullina et al , ) and in one patient with SCD who was treated with HC and everolimus (Gaudre et al , ).…”

Section: Haematological Data Of the Patients At Baseline And After Trmentioning

confidence: 99%

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Additive effect of sirolimus and hydroxycarbamide on fetal haemoglobin level in kidney transplant patients with sickle cell disease

Al-Khatti

Alkhunaizi

2018

Br J Haematol

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Section: Haematological Data Of the Patients At Baseline And After Trmentioning

confidence: 76%

Section: Haematological Data Of the Patients At Baseline And After Trmentioning

confidence: 99%

Additive effect of sirolimus and hydroxycarbamide on fetal haemoglobin level in kidney transplant patients with sickle cell disease

Al-Khatti

Alkhunaizi

2018

Br J Haematol

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“…Nowadays this drug is used as immunosuppressant in combination with other drugs (e.g. cyclosporine or corticosteroids) in the setting of prevention of transplant rejection [35,36] (see Supplementary Figure S1 for an historical summary of key actions and findings concerning sirolimus).…”

Section: Introductionmentioning

confidence: 99%

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Zuccato

Cosenza

Zurlo

et al. 2021

Preprint

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Introduction: The β-thalassemias are due to autosomal mutations of the β-globin gene, inducing absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that high production of fetal hemoglobin (HbF) is beneficial for β-thalassemia patients. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus found to be a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular and clinical results of the sirolimus-based NCT03877809 clinical trial (A Personalized Medicine Approach for β-thalassemia Transfusion Dependent Patients: Testing sirolimus in a First Pilot Clinical Trial: Sirthalaclin). Methods: Accumulation of γ-globin mRNA was analyzed by reverse-transcription-quantitative PCR and the hemoglobin pattern by HPLC. The immunophenotype was analyzed by FACS using antibodies against CD3, CD4, CD8, CD14, CD19, CD25. Results: The results were obtained in 8 patients with β+/β+ and β+/β0 genotypes, treated with a starting dosage of 1 mg/day sirolimus for 24-48 weeks. The first finding of the study was that expression of γ-globin mRNA was increased in blood and erythroid precursor cells isolated from β-thalassemia patients treated with low-dose sirolimus. A second important conclusion of our trial was that sirolimus influences erythropoiesis and reduces biochemical markers associated to ineffective erythropoiesis (I.E.) (excess of free α-globin chains, bilirubin, soluble transferrin receptor and ferritin). In most (7/8) of the patients a decrease of the transfusion index was observed. The drug was well tolerated with minor effects on immunophenotype, the only side effect being frequently occurring stomatitis. Conclusions: The data obtained indicate that sirolimus given at low doses modifies hematopoiesis and induces increased expression of γ-globin genes in a sub-set of β-thalassemia patients. Further clinical trials are warranted, considering the possibility to test the drug in patients with less severe forms of the disease and exploring combination therapies.

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“…The mTOR inhibitor, rapamycin, increases HbF levels and ameliorates the nociception phenotype in sickle cell mice (43). Gaudre et al reported a case of a kidney transplant recipient with SCD who was treated with everolimus, an mTOR inhibitor (33). At 10 mo after initiating therapy, the patient's HbF level increased dramatically from 4.8 to 15%, and there was excellent tolerance to treatment.…”

Section: Elevating Fetal Hemoglobinmentioning

confidence: 99%

Targeting pain at its source in sickle cell disease

Gupta

Jahagirdar

Gupta

2018

American Journal of Physiology-Regulatory, Integrative and Comp

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Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

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Improved Fetal Hemoglobin With mTOR Inhibitor–Based Immunosuppression in a Kidney Transplant Recipient With Sickle Cell Disease

Cited by 29 publications

References 17 publications

Additive effect of sirolimus and hydroxycarbamide on fetal haemoglobin level in kidney transplant patients with sickle cell disease

Additive effect of sirolimus and hydroxycarbamide on fetal haemoglobin level in kidney transplant patients with sickle cell disease

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Targeting pain at its source in sickle cell disease

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