Deferiprone

SOMERVILLE, Mass.--(BUSINESS WIRE)--Genetix Biotherapeutics Inc. today announced that an analysis of recent patient experience data from the commercial implementation of LYFGENIA™ and ZYNTEGLO™ in the U.S. has been selected for oral presentation at the 67th American Society of Hematology (ASH) Annual Meeting in Orlando, Florida (December 6-9, 2025). “We are pleased to share this analysis for the first time at ASH, which demonstrates the rising acceptance and administration of our one-time gene therapies.” said Joanne Lager, MD, Chief Medical Officer. “The presentation highlights the growing demand for ZYNTEGLO, the first FDA-approved gene therapy for eligible patients with transfusion-dependent beta-thalassemia and how experience from the ZYNTEGLO launch paved the way for more rapid access to LYFGENIA treatment for sickle cell patients nationwide. It also illustrates the progress along the patient journey - from enrollment to infusion. These advancements set the standard for delivery of ex vivo gene therapy in hemoglobinopathies, and reinforce the value of durable, one-time gene therapy to significantly improve patient outcomes and provide meaningful benefits to patients, providers, and payers.” Details regarding the oral presentation can be found below. Abstract Title: Accelerating Access to Gene Therapy: Lessons from Commercial Implementation in Sickle Cell Disease and Transfusion-Dependent Thalassemia (Abstract #948) Date & Time: Monday, December 8th at 4:00pm EST Please refer to the ASH 2025 online program for full session details and visit the Genetix booth (#1261) onsite. About LYFGENIA™ (lovotibeglogene autotemcel) LYFGENIA is a one-time ex-vivo lentiviral vector (LVV) gene addition therapy approved for eligible patients with sickle cell disease, in which a functional β-globin gene is added to patients’ own hematopoietic (blood) stem and progenitor cells (HSPCs). This addition results in the production of adult hemoglobin with anti-sickling properties (HbAT87Q) which has a similar oxygen-binding affinity to wild-type HbA. LYFGENIA has been shown to limit sickling of red blood cells and reduce or eliminate vaso-occlusive events (VOEs). LYFGENIA is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of VOEs. Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. LYFGENIA has not been studied in patients with more than two α-globin gene deletions. IMPORTANT SAFETY INFORMATION FOR LYFGENIA (lovotibeglogene autotemcel) Boxed WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted. Hematologic Malignancy Hematologic malignancy has occurred in patients treated with LYFGENIA (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS). The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. Patients treated with LYFGENIA may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with LYFGENIA, and integration site analysis at Months 6, 12, and as warranted. In the event that a malignancy occurs, contact Genetix Biotherapeutics at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for testing. Post-Marketing Long Term Follow-Up Study: Patients who intend to receive treatment with LYFGENIA are encouraged to enroll in the study, as available, to assess the long-term safety of LYFGENIA and the risk of malignancies occurring after treatment with LYFGENIA by calling Genetix Biotherapeutics at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion. Delayed Platelet Engraftment Delayed platelet engraftment has been observed with LYFGENIA. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with LYFGENIA to achieve platelet engraftment. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with LYFGENIA. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 109 cells/L obtained on different days by Day 43 after infusion of LYFGENIA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with LYFGENIA, provide rescue treatment with the back-up collection of CD34+ cells. Insertional Oncogenesis There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with LYFGENIA. Hypersensitivity Reactions Allergic reactions may occur with the infusion of LYFGENIA. The dimethyl sulfoxide (DMSO) or dextran 40 in LYFGENIA may cause hypersensitivity reactions, including anaphylaxis. Anti-retroviral Use Patients should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. Hydroxyurea Use Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning. Iron Chelation Drug-drug interactions between iron chelators and the mobilization process and myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of mobilization or conditioning. Do not administer myelosuppressive iron chelators (e.g., deferiprone) for 6 months post-treatment with LYFGENIA. Non-myelosuppressive iron chelation should be restarted no sooner than 3 months after LYFGENIA infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate. Interference with PCR-based Testing Patients who have received LYFGENIA are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received LYFGENIA should not be screened for HIV infection using a PCR-based assay. Adverse Reactions The most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A). Pregnancy/Lactation Advise patients of the risks associated with myeloablative conditioning agents, including on pregnancy and fertility. LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA infusion should be discussed with the treating physician. LYFGENIA is not recommended for women who are breastfeeding, and breastfeeding after LYFGENIA infusion should be discussed with the treating physician. Females and Males of Reproductive Potential A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before LYFGENIA administration. Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra-uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of LYFGENIA. Advise patients of the options for fertility preservation. Please see full Prescribing Information, including Boxed WARNING and Medication Guide for LYFGENIA. About ZYNTEGLO™ (betibeglogene autotemcel) ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene addition therapy approved for eligible patients with transfusion-dependent beta-thalassemia who require regular red blood cell (RBC) transfusions, in which functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) is added into a patient’s own HSPCs. This addition results in the production of adult hemoglobin (HbAT87Q) enabling total hemoglobin to reach normal or near normal levels. ZYNTEGLO has been shown to eliminate the need for regular RBC transfusions. ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular RBC transfusions. IMPORTANT SAFETY INFORMATION FOR ZYNTEGLO (betibeglogene autotemcel) Delayed Platelet Engraftment Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100. Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise. Risk of Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells. Risk of Insertional Oncogenesis There is a potential risk of lentiviral vector (LVV)-mediated insertional oncogenesis after treatment with ZYNTEGLO. Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted. In the event that a malignancy occurs, contact Genetix Biotherapeutics at 1 833-999-6378 for reporting and to obtain instructions on collection of samples for testing. Hypersensitivity Reactions Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis. Anti-retroviral and Hydroxyurea Use Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed. If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. Interference with Serology Testing Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR-based assay. Adverse Reactions The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia. Drug Interactions Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates. Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate. Pregnancy/Lactation Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility. ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician. ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician. Females and Males of Reproductive Potential A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration. Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO. Advise patients of the option to cryopreserve semen or ova before treatment if appropriate. Please see full Prescribing Information and Patient Information for ZYNTEGLO. About Genetix Biotherapeutics Genetix Biotherapeutics Inc. is a privately-held, commercial-stage biotechnology company dedicated to delivering genetic therapies for patients with severe rare diseases. Backed by more than 30 years of pioneering genetic therapy innovation, the company has FDA-approved treatments for sickle cell disease, β-thalassemia, and cerebral adrenoleukodystrophy that directly treat the underlying cause of disease. Genetix is committed to commercial execution, scaling patient access, and improving the treatment experience for patients and providers. Genetix is headquartered in Somerville, Massachusetts.

近日，广州医科大学王晓玲教授/冷启彬教授/邱力博士联合在《Journal for ImmunoTherapy of Cancer》上发表了一篇题为《LTO1 and YAE1 Regulate MHC-I expression via Nonsense-Mediated RNA Decay in Tumor Cells》的突破性研究，为增强肿瘤免疫治疗疗效提供了新机制和新方法。研究发现，LTO1和YAE1蛋白复合物通过调控无义介导的RNA衰减（NMD）途径，下调肿瘤细胞的主要组织相容性复合体I类（MHC-I）表达。该机制有助于肿瘤细胞逃避免疫监视。该研究进一步证实，低剂量铁螯合剂可抑制NMD功能，上调MHC-I表达，并提升免疫检查点阻断（ICB）和T细胞受体（TCR-T）疗法的效果。 研究背景 无义介导的mRNA降解（NMD）是一种翻译依赖性的监视系统，通过调控mRNA的质量和翻译水平，在发育、分化及应激等过程中维持细胞稳态。最初，NMD被发现可降解含有提前终止密码子（PTC）的mRNA，近年来研究表明，它也能调控正常转录本，从而在转录后水平广泛影响基因表达。NMD异常会导致多个物种中5%–20%的基因表达失调，并与多种人类遗传病及癌症的病理机制相关。 在肿瘤发生中，NMD具有双重作用：一方面可抑制肿瘤生长，清除编码应激反应蛋白和信号因子的正常mRNA；另一方面，NMD也可通过降解编码免疫原性新抗原的mRNA、优先靶向抑癌基因突变等方式促进肿瘤进展。因此，抑制NMD被认为可能有助于肿瘤免疫治疗，例如增强新抗原表达及恢复抑癌基因功能。 LTO1（ORAOV1）在多种实体瘤中高表达，位于肿瘤中频繁扩增的染色体区域11q13，其下调可抑制肿瘤细胞活力。LTO1与YAE1通过保守的deca-GX3基序结合，参与胞质Fe-S蛋白组装，并在酵母中调控核糖体成熟及翻译起始。值得注意的是，LTO1/YAE1的下游靶标ABCE1是已知的NMD调控因子，提示LTO1/YAE1可能通过ABCE1参与NMD过程。 核心机制研究 研究采用CRISPR/Cas9基因编辑技术，在多种肿瘤细胞系（如A375黑色素瘤和MC38结肠癌模型）中敲除LTO1、YAE1或相关因子ABCE1。结果显示，这些蛋白的缺失破坏了NMD功能，导致MHC-I调控因子（如NLRC5、IRF1和NFκB）的mRNA积累，并上调MHC-I表面表达数倍。通过荧光报告基因实验、流式细胞术（FACS）和RNA测序（RNA-seq），确认敲除后共有720个基因上调，其中包括NMD靶基因（如ATF3、GADD45A）。此外，LTO1/YAE1缺失还降低核糖体生物合成相关基因表达（如RPL7、RPL14），并改变核糖体亚基比例。 LTO1/YAE1复合物不仅参与核糖体生物合成，还通过铁硫簇组装途径调控翻译终止。研究发现，LTO1的deca-GX3基序突变体（如G38/42/46）可模拟敲除效果，表明该基序为潜在药物靶点。 免疫调控验证 在体外T细胞共培养实验中，敲除这些靶点后，CD8+ T细胞激活率增加，肿瘤杀伤效率提高约30%。在小鼠模型中，与抗PD-1抗体联合使用，进一步抑制肿瘤生长，并增加肿瘤浸润淋巴细胞（TILs）数量。 老药新靶探索 在药物干预方面，研究筛选出低剂量铁螯合剂（如去铁胺DFO和去铁酮DFX，已获FDA批准用于铁过载治疗）作为NMD抑制剂。在5-30µM浓度下，这些药物特异性阻断LTO1/YAE1介导的NMD，上调MHC-I表达。在跨物种细胞系验证中，低剂量DFO增强OT-I T细胞对MC38肿瘤的识别和杀伤。在体内实验中，与ICB联用后，肿瘤体积缩小幅度为单药治疗的2-3倍，OVA特异性TILs浸润增加。 研究结论 研究显示：LTO1/YAE1复合物通过NMD调控MHC-I表达，其抑制可提升T细胞活性并改善免疫疗法效果。该研究为MHC-I低表达肿瘤提供了干预策略。LTO1/YAE1高表达可作为生物标志物，用于患者筛选。低剂量铁螯合剂的再利用可缩短临床转化周期。同时，针对LTO1/YAE1的原创小分子或抗体药物，或可与现有ICB/TCR-T产品（如Keytruda）形成联合方案，扩展免疫疗法应用。 研究团队已提交专利，邀请制药企业洽谈授权或联合开发，以推动从实验室到临床的转化。 原文链接： https://jitc.bmj.com/lookup/doi/10.1136/jitc-2025-011893 【关于投稿】 转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！ 转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。 责任声明：本稿件如有错误之处，敬请联系转化医学网客服进行修改事宜！ 微信号：zhuanhuayixue 2025年12月09-12日 中国 • 上海