Gene Therapy for Hemoglobinopathies: Tremendous Successes and Remaining Caveats.
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ABSTRACT:
SUBMITTER: Malik P
PROVIDER: S-EPMC4886952 | biostudies-literature | 2016 Apr
REPOSITORIES: biostudies-literature
Publications
Gene Therapy for Hemoglobinopathies: Tremendous Successes and Remaining Caveats.
Molecular therapy : the journal of the American Society of Gene Therapy 20160401 4
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Project description:Gene therapy for β-thalassemia and sickle-cell disease is based on transplantation of genetically corrected, autologous hematopoietic stem cells. Preclinical and clinical studies have shown the safety and efficacy of this therapeutic approach, currently based on lentiviral vectors to transfer a β-globin gene under the transcriptional control of regulatory elements of the β-globin locus. Nevertheless, a number of factors are still limiting its efficacy, such as limited stem-cell dose and quality, suboptimal gene transfer efficiency and gene expression levels, and toxicity of myeloablative regimens. In addition, the cost and complexity of the current vector and cell manufacturing clearly limits its application to patients living in less favored countries, where hemoglobinopathies may reach endemic proportions. Gene-editing technology may provide a therapeutic alternative overcoming some of these limitations, though proving its safety and efficacy will most likely require extensive clinical investigation.
| S-EPMC6196755 | biostudies-literature
Project description:β-Thalassemia and sickle cell disease (SCD) are the world's two most widely disseminated hereditary hemoglobinopathies. β-Thalassemia originated in the Mediterranean, Middle Eastern, and Asian regions, and SCD originated in central Africa. However, subsequent population migration means that these two diseases are now global and thus constitute a growing health problem in many countries. Despite remarkable improvements in medical care for patients with β-hemoglobinopathies, there is still only one definitive treatment option: allogeneic hematopoietic stem cell (HSC) transplantation. The development of gene therapy for β-hemoglobinopathies has been justified by (1) the limited availability of human leukocyte antigen (HLA)-identical donors, (2) the narrow window of application of HSC transplantation to the youngest patients, and (3) recent advances in HSC-based gene therapy. The huge ongoing efforts in translational medicine and the high number of related publications show that gene therapy has the potential to become the treatment of choice for patients who lack either an HLA genoidentical sibling or an alternative, medically acceptable donor. In this dynamic scientific context, we first summarize the main steps toward clinical translation of this therapeutic approach and then discuss novel lentiviral- and genome editing-based treatment strategies for β-hemoglobinopathies.
| S-EPMC5417842 | biostudies-literature
Project description:Investigations to understand the function and control of the globin genes have led to some of the most exciting molecular discoveries and biomedical breakthroughs of the 20th and 21st centuries. Extensive characterization of the globin gene locus, accompanied by pioneering work on the utilization of viruses as human gene delivery tools in human hematopoietic stem and progenitor cells (HPSCs), has led to transformative and successful therapies via autologous hematopoietic stem-cell transplant with gene therapy (HSCT-GT). Due to the advanced understanding of the β-globin gene cluster, the first diseases considered for autologous HSCT-GT were two prevalent β-hemoglobinopathies: sickle cell disease and β-thalassemia, both affecting functional β-globin chains and leading to substantial morbidity. Both conditions are suitable for allogeneic HSCT; however, this therapy comes with serious risks and is most effective using an HLA-matched family donor (which is not available for most patients) to obtain optimal therapeutic and safe benefits. Transplants from unrelated or haplo-identical donors carry higher risks, although they are progressively improving. Conversely, HSCT-GT utilizes the patient's own HSPCs, broadening access to more patients. Several gene therapy clinical trials have been reported to have achieved significant disease improvement, and more are underway. Based on the safety and the therapeutic success of autologous HSCT-GT, the U.S. Food and Drug Administration (FDA) in 2022 approved an HSCT-GT for β-thalassemia (Zynteglo™). This review illuminates the β-globin gene research journey, adversities faced, and achievements reached; it highlights important molecular and genetic findings of the β-globin locus, describes the predominant globin vectors, and concludes by describing promising results from clinical trials for both sickle cell disease and β-thalassemia.
| S-EPMC10054523 | biostudies-literature
Project description:IntroductionIn a context of high HIV prevalence, poor pregnancy follow-up, frequent poverty, preeclampsia, and preterm delivery, we aimed to describe the characteristics and outcomes of pregnancies among women living with HIV in French Guiana.MethodsA retrospective cohort study was conducted on HIV-infected pregnancies enrolled between January 1st 1992 to 31st July 2022. Overall, there were 1,774 pregnancies in 881 women living with HIV.ResultsFor 75.1% of pregnancies, the HIV diagnosis was already known before pregnancy and in 67.6% of women, HIV follow-up predated pregnancy. Nearly half of women, 49.6%, only had one pregnancy since having been diagnosed with HIV. Although most women received antiretroviral therapy during pregnancy, for those with the available information we found only 48.5% had an undetectable viral load at delivery. Overall, 15.3% of pregnancies ended with an abortion. There were a total of 110 newborns infected with HIV representing an overall transmission rate of 6.2% (110/1,771). Between 1993 and 2002, the transmission rate was 34%, between 2003 and 2012 it was 1.3%, and between 2013 and 2022 it was 0.7%. Overall, in Cayenne, since 2008, 106 of 581 HIV-infected pregnancies (18.2%) with available information were premature before 37 weeks of pregnancy; of these, 33 (5.7%) were very preterm deliveries and 73 (13.3%) were late preterm deliveries. Over time, in Cayenne, preterm delivery declined significantly.ConclusionsThe present study emphasizes that, despite spectacular progress in reducing mother to child transmission, pregnancy outcomes among women living with HIV are still preoccupying with high incidence of preterm delivery and low birth weight. Teasing out what fraction is linked to HIV and what fraction is linked to social precariousness and poor follow-up was not possible in this study. Despite the high incidence of very preterm delivery recent progress suggests that coordination efforts to improve follow-up may also have improved obstetrical outcomes.
| S-EPMC10791775 | biostudies-literature
Project description:Inherited hemoglobin disorders, including beta-thalassemia (BT) and sickle-cell disease (SCD), are the most common monogenic diseases worldwide, with a global carrier frequency of over 5%.1 With migration, they are becoming more common worldwide, making their management and care an increasing concern for health care systems. BT is characterized by an imbalance in the α/β-globin chain ratio, ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hemopoietic expansion.1 Globally, there are over 25,000 births each year with transfusion-dependent thalassemia (TDT). The currently available treatment for TDT is lifelong transfusions and iron chelation therapy or allogenic bone marrow transplantation as a curative option. SCD affects 300 million people worldwide2 and severely impacts the quality of life of patients who experience unpredictable, recurrent acute and chronic severe pain, stroke, infections, pulmonary disease, kidney disease, retinopathy, and other complications. While survival has been dramatically extended, quality of life is markedly reduced by disease- and treatment-associated morbidity. The development of safe, tissue-specific and efficient vectors, and efficient gene-editing technologies have led to the development of several gene therapy trials for BT and SCD. However, the complexity of the approach presents its hurdles. Fundamental factors at play include the requirement for myeloablation on a patient with benign disease, the age of the patient, and the consequent bone marrow microenvironment. A successful path from proof-ofconcept studies to commercialization must render gene therapy a sustainable and accessible approach for a large number of patients. Furthermore, the cost of these therapies is a considerable challenge for the health care system. While new promising therapeutic options are emerging,3,4 and many others are on the pipeline,5 gene therapy can potentially cure patients. We herein provide an overview of the most recent, likely potentially curative therapies for hemoglobinopathies and a summary of the challenges that these approaches entail.
| S-EPMC6827604 | biostudies-literature
Project description:Therapeutic gene transfer holds the promise of providing lasting therapies and even cures for diseases that were previously untreatable or for which only temporary or suboptimal treatments were available. For some time, clinical gene therapy was characterized by some impressive but rare examples of successes and also several setbacks. However, effective and long-lasting treatments are now being reported from gene therapy trials at an increasing pace. Positive outcomes have been documented for a wide range of genetic diseases (including hematological, immunological, ocular, and neurodegenerative and metabolic disorders) and several types of cancer. Examples include restoration of vision in blind patients, eradication of blood cancers for which all other treatments had failed, correction of hemoglobinopathies and coagulation factor deficiencies, and restoration of the immune system in children born with primary immune deficiency. To date, about 2,000 clinical trials for various diseases have occurred or are in progress, and many more are in the pipeline. Multiple clinical studies reported successful treatments of pediatric patients. Design of gene therapy vectors and their clinical development are advancing rapidly. This article reviews some of the major successes in clinical gene therapy of recent years.
| S-EPMC4879992 | biostudies-literature
Project description:PURPOSE OF REVIEW:The introduction of the National Free Antiretroviral Therapy Program (NFATP) in 2003 by the China National Center for AIDS/STD Control and Prevention has led to dramatic increases in antiretroviral therapy (ART) coverage among HIV-infected Chinese patients. Despite limitations in the number of available free antiretroviral drugs, the overall mortality associated with HIV/AIDS has dropped from 39.3 per 100 person-years in 2002 to 3.1 in 2014. In this review, we summarize the challenges, responses, and achievements of antiretroviral therapy (ART) in China over the past 20 years. RECENT FINDINGS:Continuous optimization of the Chinese National Guidelines for HIV/AIDS Diagnosis and Treatment has been guided by data from serial domestic multi-center studies aimed at evaluating efficacy and toxicity of available ART regimens among Chinese patients with HIV, with the goal of maximizing adherence, access, and efficacy. In addition, increasing attention has been focused on the importance of continuity in the HIV care cascade to promote linkage to care, and address the multidisciplinary chronic care needs HIV/AIDS patients on lifelong ART. Great progress has been achieved in the past 20 years in terms of access to and optimization of antiretroviral treatment in China. As the number of patients receiving long-term ART continues to grow, the focus of HIV/AIDS treatment has gradually transitioned from urgent care to the management of non-AIDS-related chronic complications and control of chronic inflammation.
| S-EPMC6989417 | biostudies-literature
Project description:β-globin gene disorders are the most prevalent inherited diseases worldwide and result from abnormal β-globin synthesis or structure. Novel therapeutic approaches are being developed in an effort to move beyond palliative management. Gene therapy, by ex vivo lentiviral transfer of a therapeutic β-globin gene derivative (β(AT87Q)-globin) to hematopoietic stem cells, driven by cis-regulatory elements that confer high, erythroid-specific expression, has been evaluated in human clinical trials over the past 8 years. β(AT87Q)-globin is used both as a strong inhibitor of HbS polymerization and as a biomarker. While long-term studies are underway in multiple centers in Europe and in the United States, proof-of-principle of efficacy and safety has already been obtained in multiple patients with β-thalassemia and sickle cell disease.
| S-EPMC4779296 | biostudies-literature
Project description:The β-hemoglobinopathies sickle cell anemia and β-thalassemia are the focus of many gene-therapy studies. A key disease parameter is the abundance of globin chains because it indicates the level of anemia, likely toxicity of excess or aberrant globins, and therapeutic potential of induced or exogenous β-like globins. Reversed-phase high-performance liquid chromatography (HPLC) allows versatile and inexpensive globin quantification, but commonly applied protocols suffer from long run times, high sample requirements, or inability to separate murine from human β-globin chains. The latter point is problematic for in vivo studies with gene-addition vectors in murine disease models and mouse/human chimeras. This study demonstrates HPLC-based measurements of globin expression (1) after differentiation of the commonly applied human umbilical cord blood-derived erythroid progenitor-2 cell line, (2) in erythroid progeny of CD34+ cells for the analysis of clustered regularly interspaced short palindromic repeats/Cas9-mediated disruption of the globin regulator BCL11A, and (3) of transgenic mice holding the human β-globin locus. At run times of 8 min for separation of murine and human β-globin chains as well as of human γ-globin chains, and with routine measurement of globin-chain ratios for 12 nL of blood (tested for down to 0.75 nL) or of 300,000 in vitro differentiated cells, the methods presented here and any variant-specific adaptations thereof will greatly facilitate evaluation of novel therapy applications for β-hemoglobinopathies.
| S-EPMC5806072 | biostudies-literature
Project description:Although gene transfer to hematopoietic stem cells (HSCs) has shown therapeutic efficacy in recent trials for several individuals with inherited disorders, transduction incompleteness of the HSC population remains a hurdle to yield a cure for all patients with reasonably low integrated vector numbers. In previous attempts at HSC selection, massive loss of transduced HSCs, contamination with non-transduced cells, or lack of applicability to large cell populations has rendered the procedures out of reach for human applications. Here, we fused codon-optimized puromycin N-acetyltransferase to herpes simplex virus thymidine kinase. When expressed from a ubiquitous promoter within a complex lentiviral vector comprising the βAT87Q-globin gene, viral titers and therapeutic gene expression were maintained at effective levels. Complete selection and preservation of transduced HSCs were achieved after brief exposure to puromycin in the presence of MDR1 blocking agents, suggesting the procedure's suitability for human clinical applications while affording the additional safety of conditional suicide.
| S-EPMC5835017 | biostudies-literature