H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Int J Mol Sci. 2022 Dec 12;23(24):15750. doi: 10.3390/ijms232415750.
β-thalassemia is one of the most common monogenic disorders and a life-threatening health issue in children. A cost-effective and safe therapeutic approach to treat this disease is to reactivate the γ-globin gene for fetal hemoglobin (HbF) production that has been silenced during infancy. Hydroxyurea (HU) is the only FDA approved HbF inducer. However, its cytotoxicity and inability to respond significantly in all patients pose a need for an HbF inducer with better efficacy. The study describes the serum metabolic alteration in β-YAC transgenic mice treated with Tenofovir disoproxil fumarate (TDF) ( = 5), a newly identified HbF inducer, and compared to the mice groups treated with HU ( = 5) and untreated control ( = 5) using gas chromatography-mass spectrometry. Various univariate and multivariate statistical analyses were performed to identify discriminant metabolites that altered the biological pathways encompassing galactose metabolism, lactose degradation, and inositol. Furthermore, the decreased concentrations of L-fucose and geraniol in TDF-treated mice help in recovering towards normal, decreasing oxidative stress even much better than the HU-treated mice. The proposed study suggested that TDF can reduce the deficiency of blood required for β-thalassemia and can be used for the preclinical study at phase I/II for fetal hemoglobin production.
β-地中海贫血是最常见的单基因疾病之一，也是儿童面临的危及生命的健康问题。一种具有成本效益且安全的治疗方法是重新激活γ-珠蛋白基因，以产生在婴儿期沉默的胎儿血红蛋白 (HbF)。羟基脲 (HU) 是唯一获得 FDA 批准的 HbF 诱导剂。然而，其细胞毒性和不能显著响应所有患者的能力需要一种具有更好疗效的 HbF 诱导剂。本研究描述了用 Tenofovir disoproxil fumarate (TDF)（=5）治疗的β-YAC 转基因小鼠的血清代谢改变，TDF 是一种新鉴定的 HbF 诱导剂，并与用 HU（=5）和未处理的对照（=5）治疗的小鼠组进行比较使用气相色谱-质谱法。进行了各种单变量和多变量统计分析，以鉴定改变包含半乳糖代谢、乳糖降解和肌醇的生物途径的差异代谢物。此外，TDF 治疗的小鼠中 L-岩藻糖和香叶醇浓度降低有助于恢复正常，甚至比 HU 治疗的小鼠更能降低氧化应激。该研究表明，TDF 可以减少β-地中海贫血所需的血液不足，可以用于 I/II 期临床前研究以产生胎儿血红蛋白。
