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 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 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 The Rise of SARS-CoV-2 Variants and the Role of Convalescent Plasma Therapy for Management of Infections

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 734
Author(s):  
Mohamed Moubarak ◽  
Keneth Iceland Kasozi ◽  
Helal F. Hetta ◽  
Hazem M. Shaheen ◽  
Abdur Rauf ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Survival Rates ◽  
H1n1 Influenza ◽  
Host Responses ◽  
Novel Therapies ◽  
Clotting Factors ◽  
Plasma Therapy ◽  
Community Transmission

Novel therapies for the treatment of COVID-19 are continuing to emerge as the SARS-Cov-2 pandemic progresses. PCR remains the standard benchmark for initial diagnosis of COVID-19 infection, while advances in immunological profiling are guiding clinical treatment. The SARS-Cov-2 virus has undergone multiple mutations since its emergence in 2019, resulting in changes in virulence that have impacted on disease severity globally. The emergence of more virulent variants of SARS-Cov-2 remains challenging for effective disease control during this pandemic. Major variants identified to date include B.1.1.7, B.1.351; P.1; B.1.617.2; B.1.427; P.2; P.3; B.1.525; and C.37. Globally, large unvaccinated populations increase the risk of more and more variants arising. With successive waves of COVID-19 emerging, strategies that mitigate against community transmission need to be implemented, including increased vaccination coverage. For treatment, convalescent plasma therapy, successfully deployed during recent Ebola outbreaks and for H1N1 influenza, can increase survival rates and improve host responses to viral challenge. Convalescent plasma is rich with cytokines (IL-1β, IL-2, IL-6, IL-17, and IL-8), CCL2, and TNFα, neutralizing antibodies, and clotting factors essential for the management of SARS-CoV-2 infection. Clinical trials can inform and guide treatment policy, leading to mainstream adoption of convalescent therapy. This review examines the limited number of clinical trials published, to date that have deployed this therapy and explores clinical trials in progress for the treatment of COVID-19.

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.

Cardiac disease: Current approaches to gene therapy

2020 ◽  
pp. 62-75
Author(s):  
Reyad ul-ferdous ◽  
◽  
Shofiul Azam ◽  
◽  
◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Cardiac Disease ◽  
Target Genes ◽  
Viral Vector ◽  
Delivery Methods ◽  
Gene Therapies ◽  
Inherited Cardiomyopathies

Background: Last decade over the world, the cardiac disease becomes a leading cause of death. Gene-based therapies become a promising treatment for patients affected by cardiovascular diseases, such as myocardial infarction (MI), arteriosclerosis, heart failure and so on, but also underline the require for reproducible results in preclinical and clinical studies for efficacy and safety. Aim: This book chapter describes the current research prospect of gene therapy for cardiac disease. We focus on the various models to deliver genes using viral, non-viral vector, delivery methods, targets gene, recent clinical trials, inherited cardiomyopathies target genes and Present advances of CRISPR/Cas 9 for cardiovascular gene therapy. We recapitulate some challenges that require being overcome, future directions of gene therapies for cardiac disease. Materials and Methods: All required information regards Lef-7 was generated by exploring the internet search engine like as (PubMed, Wiley, ScienceDirect, CNKI, ACS, Google Scholar, Web of Science, SciFinder, and Baidu Scholar) and libraries. Results: In this book chapter, we focus on the present prospect of gene targets, gene delivery methods, and efficient vector to deliver gene, targets gene, recent clinical trials, inherited cardiomyopathies target genes and present advances of CRISPR/Cas 9 technology for the treatment of cardiac disease using gene therapy. Recent clinical trials require modifying vectors and gene delivery approaches to achieve effective results for cardiac gene therapy. Conclusion: In this book chapter, we integrate a historical perspective with recent advances that will likely affect clinical development in this research area.

Hemophilia Gene Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-48-SCI-48
Author(s):  
Valder R. Arruda
Keyword(s):  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
Biological Activities ◽  
Ectopic Expression ◽  
Clotting Factor ◽  
Dependent Manner ◽  
Disease Phenotype ◽  
Clotting Factors ◽  
Hematopoietic Stem

Abstract SCI-48 Over the last decade, five clinical studies on gene therapy for hemophilia A and B using viral and nonviral vectors for liver-restricted or ectopic expression of clotting factor demonstrated safety with no inhibitor formation. Although efficacy in these early phase trials was not achieved because of sustained levels of clotting factor below 1%, these studies form the basis for the second generation of clinical trials. To date, two studies on adeno-associated viral (AAV) vector encoding a FIX transgene for liver-restricted expression are ongoing. In one study using a modified AAV genome pseudotyped with serotype 8, emerging data are encouraging and sustained therapeutic levels of FIX have been obtained in a dose-dependent manner. Novel approaches for hemophilia have been explored targeting hematopoietic stem cells (HSC) using lentiviral vectors for expressing FVIII or FIX genes. Transgene expression under the control of either a non-lineage specific promoter or a platelet-specific promoter showed biological activity and improvement of the disease phenotype. The platelet-restricted approaches did not increase circulating plasma clotting factor levels, but they resulted in enrichment of the factor at the injury site upon platelet activation. An advantage of targeting FVIII expression and storage in platelets is the protection of FVIII from neutralizing antibodies (inhibitors). In this model, platelet-FVIII provided superior hemostasis than elevated plasma FVIII levels upon hemostatic challenges in the microcirculation and macrocirculation. Recently, platelet-restricted expression of human FVIII gene using a lentiviral vector for ex vivo transduction of canine HSC resulted in improvement of the disease phenotype in severe hemophilia A dogs without unwanted immune responses to the transgene. Additional strategies to optimize gene- and/or cell-based approaches have also focused on use of clotting factors with enhanced biological activities will be discussed. Together with the generation of novel vectors, further enhancement of both the efficacy the safety of these approaches is envisioned. Disclosures: Arruda: Pfizer: Research Funding.

scholarly journals Schwannoma Gene Therapy via Adeno-Associated Viral Vector Delivery of Apoptosis-Associated Speck-like Protein Containing CARD (ASC): Preclinical Efficacy and Safety

2022 ◽  
Vol 23 (2) ◽  
pp. 819
Author(s):  
Sherif G. Ahmed ◽  
Casey A. Maguire ◽  
Shiliang Alice Cao ◽  
Gary J. Brenner
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Viral Vector ◽  
Cranial Nerves ◽  
Adaptor Protein ◽  
Primary Treatment ◽  
Motor Dysfunction ◽  
Therapy Strategy ◽  
Virus Serotype ◽  
Immunocompetent Mice

Schwannomas are tumors derived from Schwann-lineage cells, cells that protect and support myelinated nerves in the peripheral nervous system. They are typically slow-growing, encapsulated and benign. These tumors develop along peripheral, spinal and cranial nerves causing pain, sensory-motor dysfunction and death. Primary treatment for schwannoma is operative resection which can be associated with significant morbidity. Pharmacotherapy is largely restricted to bevacizumab, which has minimal or no efficacy for many patients and can be associated with treatment-limiting adverse effects. Given the suffering and morbidity associated with schwannoma and the paucity of therapeutic options, there is an urgent need for safe and effective therapies for schwannomas. We previously demonstrated that adeno-associated virus serotype 1 (AAV1) vector mediated delivery of the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) under the control of the P0 promoter, produced a prolonged reduction in tumor volume and tumor-associated pain in human xenograft and mouse syngeneic schwannoma models. Here, we present data essential for the translation of our AAV1-P0-ASC schwannoma gene therapy to clinical trials. We determine the minimum effective dose of AAV1-P0-hASC required to induce an anti-tumor effect in the xenograft human-schwannoma model. We also show that the presence of preexisting AAV1 immunity does not alter the antitumor efficacy of AAV-P0-mASC in a syngeneic mouse schwannoma model. Furthermore, the maximum deliverable intratumoral dose of AAV1-P0-ASC was not associated with neuronal toxicity in immunocompetent mice. Taken together, these safety and efficacy data support the translation of the AAV1-P0-ASC schwannoma gene therapy strategy to clinical trials.

scholarly journals Review of preventative HIV vaccine clinical trials in South Africa

2020 ◽  
Vol 165 (11) ◽  
pp. 2439-2452
Author(s):  
Fatima Laher ◽  
Linda-Gail Bekker ◽  
Nigel Garrett ◽  
Erica M. Lazarus ◽  
Glenda E. Gray
Keyword(s):  
South Africa ◽  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Viral Vectors ◽  
Viral Vector ◽  
Passive Immunization ◽  
Hiv Infections ◽  
Aluminum Phosphate ◽  
Hiv Vaccine ◽  
Subtype C

AbstractNew HIV infections continue relentlessly in southern Africa, demonstrating the need for a vaccine to prevent HIV subtype C. In South Africa, the country with the highest number of new infections annually, HIV vaccine research has been ongoing since 2003 with collaborative public-private-philanthropic partnerships. So far, 21 clinical trials have been conducted in South Africa, investigating seven viral vectors, three DNA plasmids, four envelope proteins, five adjuvants and three monoclonal antibodies. Active vaccine candidates have spanned subtypes A, B, C, E and multi-subtype mosaic sequences. All were well tolerated. Four concepts were investigated for efficacy: rAd5-gag/pol/nef showed increased HIV acquisition in males, subtype C ALVAC/gp120/MF59 showed no preventative efficacy, and the trials for the VRC01 monoclonal antibody and Ad26.Mos4.HIV/subtype C gp140/ aluminum phosphate are ongoing. Future trials are planned with DNA/viral vector plus protein combinations in concert with pre-exposure prophylaxis, and sequential immunization studies with transmitted/founder HIV envelope to induce broadly neutralizing antibodies. Finally, passive immunization trials are underway to build on the experience with VRC01, including single and combination antibody trials with an antibody derived from a subtype-C-infected South African donor. Future consideration should be given to the evaluation of novel strategies, for example, inactivated-whole-virus vaccines.

scholarly journals GENE THERAPY FOR OBSTETRIC CONDITIONS

2014 ◽  
Vol 25 (3-4) ◽  
pp. 147-177
Author(s):  
REBECCA N. SPENCER ◽  
DAVID J. CARR ◽  
ANNA L. DAVID
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Lipoprotein Lipase ◽  
Molecular Mechanisms ◽  
Viral Vector ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Nasopharyngeal Cancer ◽  
New Paradigm ◽  
Gene Therapies

The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy.

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