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

Al-Khatti, Adil A.; Alkhunaizi, Ahmed M.

doi:10.1111/bjh.15665

Cited by 17 publications

(21 citation statements)

References 15 publications

(21 reference statements)

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“…Sirolimus treatment prolonged the lifespan of sickle cell erythrocytes in circulation, reduced spleen size, and reduced renal and hepatic iron accumulation in SCD mice [34]. Third, sirolimus or sirolimus analogues (either alone or in combination with hydroxycarbamide) induced HbF production in patients treated who underwent kidney transplantation [35,36]. These studies demonstrated that in SCD patients treated with sirolimus or sirolimus analogues the HbF level was dramatically increased.…”

Section: Discussionmentioning

confidence: 94%

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

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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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Section: Discussionmentioning

confidence: 94%

“…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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show abstract

“… 34 Third, sirolimus or sirolimus analogs (either alone or in combination with hydroxycarbamide) induced HbF production in patients treated with kidney transplantation. 35 , 36 These studies demonstrated that in SCD patients treated with sirolimus or sirolimus analogs, there was a dramatic increase in the HbF level.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, this drug is used as an immunosuppressant in combination with other drugs (e.g. cyclosporine or corticosteroids) to prevent transplant rejection 35 , 36 (see Supplementary Figure S1 for a 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. 2022

Therapeutic Advances in Hematology

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Introduction: β-thalassemia is caused by autosomal mutations in the β-globin gene, which induce the absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that a high production of fetal hemoglobin (HbF) is beneficial for patients with β-thalassemia. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus that serves as a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular, and clinical results of a 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 using reverse-transcription quantitative polymerase chain reaction (PCR), while the hemoglobin pattern was analyzed using high-performance liquid chromatography (HPLC). The immunophenotype was analyzed using a fluorescence-activated cell sorter (FACS), with antibodies against CD3, CD4, CD8, CD14, CD19, CD25 (for analysis of peripheral blood mononuclear cells), or CD71 and CD235a (for analysis of in vitro cultured erythroid precursors). Results: The results were obtained in eight patients with the β+/β+ and β+/β0 genotypes, who were treated with a starting dosage of 1 mg/day sirolimus for 24–48 weeks. The first finding of this study was that the expression of γ-globin mRNA increased in the blood and erythroid precursor cells isolated from β-thalassemia patients treated with low-dose sirolimus. This trial also led to the important finding that sirolimus influences erythropoiesis and reduces biochemical markers associated with ineffective erythropoiesis (excess free α-globin chains, bilirubin, soluble transferrin receptor, and ferritin). A decrease in the transfusion demand index was observed in most (7/8) of the patients. The drug was well tolerated, with minor effects on the immunophenotype, and an only side effect of frequently occurring stomatitis. Conclusion: The data obtained indicate that low doses of sirolimus modify hematopoiesis and induce increased expression of γ-globin genes in a subset of patients with β-thalassemia. Further clinical trials are warranted, possibly including testing of the drug in patients with less severe forms of the disease and exploring combination therapies.

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“…In an effort for bringing sirolimus to possible clinical evaluation, applications were filed in EU and in USA, obtaining ODD designation by EMA (Treatment of β-thalassaemia intermedia and major, December 2015) and by FDA (Treatment of β-thalassemia, June 2016). Apart from the data generated by in vitro studies, several groups provided evidence supporting the use of this established drugs in β-thalassemia through experiments in animal model [54][55][56][57] and reporting an increase level of HbF in clinical settings 58,59 .…”

Section: Drug Repositioning For Rare Diseases: β-Thalassemiamentioning

confidence: 99%

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

et al. 2022

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Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', ‘drug rescue’, ‘drug re-tasking’ and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the “off-label” use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.

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

Cited by 17 publications

References 15 publications

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

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

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

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

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