scholarly journals Gene therapy for haemophilia: an update on progress in clinical trials

2015 ◽  
Vol 2 (1) ◽  
pp. 3-5
Author(s):  
Sarah Gilgunn
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Replacement Therapy ◽  
Viral Vector ◽  
Effective Means ◽  
Clotting Factor ◽  
Haemophilia A ◽  
Spontaneous Bleeding ◽  
Factor Gene ◽  
Highly Effective

Abstract Clotting factor replacement therapy has proven a highly effective means of treating haemophilia A and B. But treatment involves frequent and lifelong infusion of factor concentrates and is generally prophylactic rather than curative. It is also extremely expensive, associated with inhibitor formation and does not fully abolish the potential for spontaneous bleeding. Gene therapy offers a potential cure for haemophilia, with the possible continuous expression of a clotting factor gene following the administration of a viral vector carrying the appropriate gene. Recent clinical trials of gene therapy for haemophilia have proven positive in selected patients and new studies are underway.

scholarly journals Gene therapy for haemophilia: a very modern success story

2015 ◽  
Vol 2 (2) ◽  
pp. 26-28
Author(s):  
Amit Nathwani
Keyword(s):  
Gene Therapy ◽  
Clotting Factor ◽  
Haemophilia A ◽  
Single Administration ◽  
Success Story ◽  
Spontaneous Bleeding ◽  
Bleeding Episodes ◽  
Paradigm Shifting

Abstract AAV-mediated gene therapy has the potential to be paradigm shifting as a treatment for haemophilia. A single administration of AAV vector can result in safe and consistent long-term expression of transgene (>5 years), reduction in spontaneous bleeding episodes, reduction in clotting factor usage and an improvement in quality of life. There is huge commercial interest in this approach, with the expectation that an AAV gene therapy product for haemophilia B will be licensed by 2020.

scholarly journals Etranacogene dezaparvovec for hemophilia B gene therapy

2021 ◽  
Vol 2 ◽  
pp. 263300402110588
Author(s):  
Courtney D. Thornburg
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Continuous Production ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Plain Language ◽  
Long Term Follow Up

The treatment landscape for hemophilia has been rapidly changing with introduction of novel therapies. Gene therapy for hemophilia is a promising therapeutic option for sustained endogenous factor production to mitigate the need for prophylactic treatment to prevent spontaneous and traumatic bleeding. Etranacogene dezaparvovec is an investigational factor IX (FIX) gene transfer product that utilizes the adeno-associated virus (AAV) 5 vector with a liver-specific promoter and a hyperactive FIX transgene. Here, the development of etranacogene dezaparvovec and available efficacy and safety data from clinical trials are reviewed. Overall, etranacogene dezaparvovec provides sustained FIX expression for more than 2 years and allows for a bleed and infusion-free life in the majority of patients. Safety, efficacy, and quality-of-life data will inform shared decision-making for patients who are considering gene therapy. Long-term follow-up regarding duration of expression and safety are crucial. Plain Language Summary Factor IX Padua gene therapy to boost clotting factor and prevent bleeding for people living with hemophilia B People living with hemophilia have low or missing clotting factor, which can lead to bleeding that is unexpected or caused by a traumatic event (such as a sports injury or surgery). There are two main types of hemophilia: clotting factor (F)VIII deficiency (known as hemophilia A) and FIX deficiency (known as hemophilia B). People living with the severe or moderately severe forms of hemophilia (clotting factor levels below 3% of normal) need regular treatment, typically by infusions into the vein, to stop or prevent bleeding and damage to their joints. Gene therapy is currently being investigated as a new treatment option that introduces a working copy of the clotting factor gene to the liver. Following treatment, clotting factor is produced by the liver. Etranacogene dezaparvovec [Et-ra-na-co-gene dez-a-par-vo-vec] is a form of gene therapy for people living with hemophilia B. This form of gene therapy includes a modified form of FIX (FIX Padua) which produces high levels of FIX activity compared with normal FIX. It is being tested to see whether individuals will have low rates of bleeding and not need to treat themselves with clotting factor. In the clinical trials, participants with FIX levels below 2% (of normal) receive a single gene therapy infusion. The results of the trials have so far shown that patients given etranacogene dezaparvovec have continuous production of FIX, whereby they have reported much less bleeding and factor treatment. Questions relating to the safety of the gene therapy and how long it works will hopefully be answered through long-term follow-up of the patients once the trials are completed.

scholarly journals Gene therapy for hemophilia: what does the future hold?

2018 ◽  
Vol 9 (9) ◽  
pp. 273-293 ◽  
Author(s):  
Bhavya S. Doshi ◽  
Valder R. Arruda
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Viral Vector ◽  
Young Patients ◽  
Clotting Factors ◽  
Liver Transaminase ◽  
Long Term Follow Up ◽  
Recent Phase ◽  
Universal Applicability

Recent phase I/II adeno-associated viral vector-mediated gene therapy clinical trials have reported remarkable success in ameliorating disease phenotype in hemophilia A and B. These trials, which highlight the challenges overcome through decades of preclinical and first in human clinical studies, have generated considerable excitement for patients and caregivers alike. Optimization of vector and transgene expression has significantly improved the ability to achieve therapeutic factor levels in these subjects. Long-term follow-up studies will guide standardization of the approach with respect to the combination of serotype, promoter, dose, and manufacturing processes and inform safety for inclusion of young patients. Certain limitations preclude universal applicability of gene therapy, including transient liver transaminase elevations due to the immune responses to vector capsids or as yet undefined mechanisms, underlying liver disease from iatrogenic viral hepatitis, and neutralizing antibodies to clotting factors. Integrating vectors show promising preclinical results, but manufacturing and safety concerns still remain. The prospect of gene editing for correction of the underlying mutation is on the horizon with considerable potential. Herein, we review the advances and limitations that have resulted in these recent successful clinical trials and outline avenues that will allow for broader applicability of gene therapy.

scholarly journals The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome

2019 ◽  
Vol 9 (2) ◽  
pp. 32 ◽  
Author(s):  
David Hampson ◽  
Alexander Hooper ◽  
Yosuke Niibori
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Fragile X Syndrome ◽  
Viral Vectors ◽  
Viral Vector ◽  
Fragile X ◽  
Animal Models Of Disease ◽  
Key Issues ◽  
Full Correction ◽  
Models Of Disease

Viral vector-mediated gene therapy has grown by leaps and bounds over the past several years. Although the reasons for this progress are varied, a deeper understanding of the basic biology of the viruses, the identification of new and improved versions of viral vectors, and simply the vast experience gained by extensive testing in both animal models of disease and in clinical trials, have been key factors. Several studies have investigated the efficacy of adeno-associated viral (AAV) vectors in the mouse model of fragile X syndrome where AAVs have been used to express fragile X mental retardation protein (FMRP), which is missing or highly reduced in the disorder. These studies have demonstrated a range of efficacies in different tests from full correction, to partial rescue, to no effect. Here we provide a backdrop of recent advances in AAV gene therapy as applied to central nervous system disorders, outline the salient features of the fragile X studies, and discuss several key issues for moving forward. Collectively, the findings to date from the mouse studies on fragile X syndrome, and data from clinical trials testing AAVs in other neurological conditions, indicate that AAV-mediated gene therapy could be a viable strategy for treating fragile X syndrome.

scholarly journals Alternative Strategies for Gene Therapy of Hemophilia

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 197-202 ◽  
Author(s):  
Robert R. Montgomery ◽  
Qizhen Shi
Keyword(s):  
Gene Therapy ◽  
Endothelial Cells ◽  
Replacement Therapy ◽  
Hemophilia A ◽  
Ectopic Expression ◽  
Factor Vii ◽  
Clotting Factor ◽  
Large Animal ◽  
Clotting Factors ◽  
Hematopoietic Stem

Abstract Hemophilia A and B are monogenic disorders that were felt to be ideal targets for initiation of gene therapy. Although the first hemophilia gene therapy trial has been over 10 years ago, few trials are currently actively recruiting. Although preclinical studies in animals were promising, levels achieved in humans did not achieve long-term expression at adequate levels to achieve cures. Transplantation as a source of cellular replacement therapy for both hemophilia A and B have been successful following liver transplantation in which the recipient produces normal levels of either factor VIII (FVIII) or factor IX (FIX). Most of these transplants have been conducted for the treatment of liver failure rather than for “curing” hemophilia. There are a variety of new strategies for delivering the missing clotting factor through ectopic expression of the deficient protein. One approach uses hematopoietic stem cells using either a nonspecific promoter or using a lineage-specific promoter. An alternative strategy includes enhanced expression in endothelial cells or blood-outgrowth endothelial cells. An additional approach includes the expression of FVIII or FIX intraarticularly to mitigate the intraarticular bleeding that causes much of the disability for hemophilia patients. Because activated factor VII (FVIIa) can be used to treat patients with inhibitory antibodies to replacement clotting factors, preclinical gene therapy has been performed using platelet- or liver-targeted FVIIa expression. All of these newer approaches are just beginning to be explored in large animal models. Whereas improved recombinant replacement products continue to be the hallmark of hemophilia therapy, the frequency of replacement therapy is beginning to be addressed through longer-acting replacement products. A safe cure of hemophilia is still the desired goal, but many barriers must still be overcome.

scholarly journals Engineered T cell therapies

2015 ◽  
Vol 17 ◽  
Author(s):  
Anne-Christine Field ◽  
Waseem Qasim
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
T Cell ◽  
Viral Vector ◽  
Ex Vivo ◽  
Immune Disorders ◽  
Clinical Experiences ◽  
Cell Therapies ◽  
Cell Gene

Alongside advancements in gene therapy for inherited immune disorders, the need for effective alternative therapeutic options for other conditions has resulted in an expansion in the field of research for T cell gene therapy. T cells are easily obtained and can be induced to divide robustly ex vivo, a characteristic that allows them to be highly permissible to viral vector-mediated introduction of transgenes. Pioneering clinical trials targeting cancers and infectious diseases have provided safety and feasibility data and important information about persistence of engineered cells in vivo. Here, we review clinical experiences with γ-retroviral and lentiviral vectors and consider the potential of integrating transposon-based vectors as well as specific genome editing with designer nucleases in engineered T cell therapies.

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