scholarly journals Gene Therapy for Inherited Bleeding Disorders

2021 ◽  
Vol 47 (02) ◽  
pp. 161-173
Author(s):  
Valder R. Arruda ◽  
Jesse Weber ◽  
Benjamin J. Samelson-Jones
Keyword(s):  
Gene Therapy ◽  
Clinical Studies ◽  
Viral Vectors ◽  
Von Willebrand Disease ◽  
Factor Ix ◽  
Factor Vii ◽  
Bleeding Disorders ◽  
Recent Success ◽  
Multiple Challenges ◽  
Therapy Field

AbstractDecades of preclinical and clinical studies developing gene therapy for hemophilia are poised to bear fruit with current promising pivotal studies likely to lead to regulatory approval. However, this recent success should not obscure the multiple challenges that were overcome to reach this destination. Gene therapy for hemophilia A and B benefited from advancements in the general gene therapy field, such as the development of adeno-associated viral vectors, as well as disease-specific breakthroughs, like the identification of B-domain deleted factor VIII and hyperactive factor IX Padua. The gene therapy field has also benefited from hemophilia B clinical studies, which revealed for the first time critical safety concerns related to immune responses to the vector capsid not anticipated in preclinical models. Preclinical studies have also investigated gene transfer approaches for other rare inherited bleeding disorders, including factor VII deficiency, von Willebrand disease, and Glanzmann thrombasthenia. Here we review the successful gene therapy journey for hemophilia and pose some unanswered questions. We then discuss the current state of gene therapy for these other rare inherited bleeding disorders and how the lessons of hemophilia gene therapy may guide clinical development.

scholarly journals Platelet Function Disorder Is More Common Than Von Willebrand Disease in Women with Inherited Bleeding Disorders: Report from a Public Sector University in Pakistan

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4937-4937
Author(s):  
Nazli Hossain ◽  
Tahir S. Shamsi ◽  
Arshi Naz ◽  
Sidra Abbas ◽  
Nazeer Khan
Keyword(s):  
Platelet Function ◽  
Conflicts Of Interest ◽  
Autosomal Recessive Inheritance ◽  
Marrow Transplant ◽  
Von Willebrand Disease ◽  
Factor Ix ◽  
Factor Vii ◽  
Cycle Duration ◽  
Bleeding Disorders ◽  
Von Willebrand

Abstract Introduction: Inherited bleeding disorders are an important cause of menorrhagia. Aim: To determine the prevalence of inherited bleeding disorders in women with menorrhagia in the absence of systemic and pelvic pathologies. Methods: The study period was from March 2013 to September 2018. It was carried out at the Department of Obstetrics & Gynecology, Unit II, Dow Medical College and Ruth Pfau KM Civil Hospital in Karachi. The laboratory investigations were carried out partly at Dow Diagnostic Research Laboratory and mainly at the National Institute of Blood Disease & Bone Marrow Transplant. Included in the study were young girls and women who presented with menorrhagia at menarche or in the later years of reproduction, with normal bimanual pelvic examination and pelvic ultrasound results. Results: Approximately 200 women with a mean menstrual cycle duration of 9.3+ 3.5 days were included. The mean age of the included patients was 32 years. Married women's partners were cousins in 50% of the women, while unmarried girls' parents were cousins in all cases. Platelet aggregation defect was presented in 33 (16.6%) women, von Willebrand disease in 26 (13.1%) women, factor IX deficiency in 20 (10%) women, combined defects in 29 (14.6%) women, and factor VII and VIII deficiencies in 4 and 11 (2%, 5.5%) women, respectively. Isolated defect with ADP, epinephrine, and collagen were decreased in 35 (17.6%), 41 (20%), and 33 (16%) women, respectively. Conclusion: Inherited bleeding disorders were a common cause of menorrhagia in our population. Consanguinity was frequently seen in these subjects. Except for some forms of VWD, all other disorders have an autosomal recessive inheritance pattern. After excluding gynecological and medical causes, a work up for inherited bleeding disorders should be advised. Keywords: menorrhagia, platelet function disorder, inherited bleeding disorders, Pakistan. Disclosures No relevant conflicts of interest to declare.

Factor VIIa-antithrombin complex: a possible new biomarker for activated coagulation

2017 ◽  
Vol 55 (4) ◽  
Author(s):  
Luca Spiezia ◽  
Elena Campello ◽  
Fabio Dalla Valle ◽  
Barry Woodhams ◽  
Paolo Simioni
Keyword(s):  
Clinical Studies ◽  
Plasma Levels ◽  
Factor Viia ◽  
Transmembrane Protein ◽  
Thrombotic Event ◽  
Factor Ix ◽  
Factor Vii ◽  
Circulating Levels ◽  
Coagulation Pathway

AbstractThe activation of the extrinsic coagulation pathway occurs after endothelial injury when the tissue factor (TF), a transmembrane protein located outside the vasculature, binds factor VII (FVII) or activated FVII (FVIIa). Once formed, the TF-VIIa complex activates both factor IX and X and initiates the coagulation process. The TF-VIIa complex is inhibited by both TF pathway inhibitor (TFPI) and antithrombin (AT). The interaction between TF-VIIa and AT induces FVIIa-AT complex formation, which is released into the plasma. Because AT reacts with FVIIa only when it is bound to TF, the circulating levels of FVIIa-AT reflect the degree of exposure of TF to blood. Preliminary clinical studies have shown higher plasma levels of FVIIa-AT complex both in patients with a prior arterial or venous thrombotic event. Increased plasma levels of FVIIa-AT have also been reported in a number of other prothrombotic conditions – antiphospholipid antibodies, solid and hematological malignancies, pre-eclampsia (PE), obesity and cardiac surgery. However, most of the studies published so far are retrospective and with a limited sample size. Larger prospective clinical studies are needed to confirm these findings and to assess the prognostic role of this possible new biomarker for activated coagulation.

scholarly journals The Use of Viral Vectors in Gene Transfer Therapy

2016 ◽  
Vol 8 (03) ◽  
Author(s):  
A. Dziaková ◽  
A. Valenčáková ◽  
E. Hatalová ◽  
J. Kalinová
Keyword(s):  
Gene Therapy ◽  
Plasmid Dna ◽  
Clinical Studies ◽  
Viral Vectors ◽  
Disease Gene ◽  
Major Gene ◽  
Genetic Material ◽  
The Body ◽  
Disease Genes ◽  
Wide Range

Gene therapy is strategy based on using genes as pharmaceuticals. Gene therapy is a treatment that involves altering the genes inside body's cells to stop disease. Genes contain DNA- the code controlling body form and function. Genes that do not work properly can cause disease. Gene therapy replaces a faulty gene or adds a new gene in an attempt to cure disease or improve the ability of the body to fight disease. Gene therapy holds promise for treating a wide range of diseases, including cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS. Various types of genetic material are used in gene therapy; double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), plasmid DNA and antisense oligodeoxynucleotides (ASON). The success of gene therapy depends on assuring the entrance of the therapeutic gene to targeted cells without any form of biodegradation. Commonly used vectors in gene therapy are: adenoviruses (400 clinical studies; 23.8%), retroviruses (344 clinical studies; 20.5%), unenveloped/plasmid DNA (304 clinical studies, 17.7%), adenoassociated viruses (75 clinical studies; 4.5%) and others. In this paper, we have reviewed the major gene delivery vectors and recent improvements made in their design meant to overcome the issues that commonly arise with the use of gene therapy vectors.

Entering the Modern Era of Gene Therapy

2019 ◽  
Vol 70 (1) ◽  
pp. 273-288 ◽  
Author(s):  
Xavier M. Anguela ◽  
Katherine A. High
Keyword(s):  
Gene Therapy ◽  
Clinical Research ◽  
Clinical Studies ◽  
Single Gene ◽  
Regulatory Approval ◽  
Gene Therapies ◽  
Single Gene Disorders ◽  
Therapy Field ◽  
Modern Era

Gene therapies are gaining momentum as promising early successes in clinical studies accumulate and examples of regulatory approval for licensing increase. Investigators are advancing with cautious optimism that effective, durable, and safe therapies will provide benefit to patients—not only those with single-gene disorders but those with complex acquired diseases as well. While the strategies being translated from the lab to the clinic are numerous, this review focuses on the clinical research that has forged the gene therapy field as it currently stands.

scholarly journals Cationic Polyene Phospholipids as DNA Carriers for Ocular Gene Therapy

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Susana Machado ◽  
Sofia Calado ◽  
Diogo Bitoque ◽  
Ana Vanessa Oliveira ◽  
Christer L. Øpstad ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Inflammatory Responses ◽  
Transfection Efficiency ◽  
Systemic Circulation ◽  
Nucleic Acid Delivery ◽  
Rpe Cells ◽  
Recent Success ◽  
Good Target ◽  
Dna Carriers

Recent success in the treatment of congenital blindness demonstrates the potential of ocular gene therapy as a therapeutic approach. The eye is a good target due to its small size, minimal diffusion of therapeutic agent to the systemic circulation, and low immune and inflammatory responses. Currently, most approaches are based on viral vectors, but efforts continue towards the synthesis and evaluation of new nonviral carriers to improve nucleic acid delivery. Our objective is to evaluate the efficiency of novel cationic retinoic and carotenoic glycol phospholipids, designated C20-18, C20-20, and C30-20, to deliver DNA to human retinal pigmented epithelium (RPE) cells. Liposomes were produced by solvent evaporation of ethanolic mixtures of the polyene compounds and coformulated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol (Chol). Addition of DNA to the liposomes formed lipoplexes, which were characterized for binding, size, biocompatibility, and transgene efficiency. Lipoplex formulations of suitable size and biocompatibility were assayed for DNA delivery, both qualitatively and quantitatively, using RPE cells and a GFP-encoding plasmid. The retinoic lipoplex formulation with DOPE revealed a transfection efficiency comparable to the known lipid references 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl]-cholesterol (DC-Chol) and 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EPC) and GeneJuice. The results demonstrate that cationic polyene phospholipids have potential as DNA carriers for ocular gene therapy.

scholarly journals Viral-Vector Delivered anti-Angiogenic Therapies to the Eye

2020 ◽  
Author(s):  
Sanna Koponen ◽  
Emmi Kokki ◽  
Kati Kinnunen ◽  
Seppo Ylä-Herttuala
Keyword(s):  
Gene Therapy ◽  
Clinical Studies ◽  
Viral Vectors ◽  
Vision Loss ◽  
Viral Vector ◽  
Great Promise ◽  
Ocular Neovascularization ◽  
Vessel Growth ◽  
Lentivirus Vectors ◽  
Endothelial Growth Factors

Pathological vessel growth harms vision and may finally lead to vision loss. Anti-angiogenic gene therapy with viral vectors for ocular neovascularization has shown great promise in pre-clinical studies. Most of the studies has conducted with different adeno-associate serotype vectors. In addition, Adeno and lentivirus vectors have been used. Therapy has targeted to block vascular endothelial growth factors or other pro-angiogenic factors. Clinical trials of intraocular gene therapy for neovascularization have shown the treatment to be safe without severe adverse events or systemic effects. Nevertheless, clinical studies have not proceeded phase 2 trials further.

Is a Pbac-Score a Good Tool to Quantify Menorrhagia in Women with Von Willebrand Disease and Rare Bleeding Disorders?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1133-1133
Author(s):  
Susan Halimeh ◽  
Hannelore Rott ◽  
Manuela Siebert ◽  
Guenther Kappert
Keyword(s):  
Blood Loss ◽  
Bleeding Disorder ◽  
Von Willebrand Disease ◽  
Factor Vii ◽  
Menstrual Blood ◽  
Cycle Period ◽  
Coagulation Disorder ◽  
Bleeding Disorders ◽  
Menstrual Blood Loss ◽  
Von Willebrand

Abstract Abstract 1133 Introduction: Von Willebrand disease (VWD) is the most common inherited bleeding disorder. VWD and other autosomal inherited bleeding disorders equally affect women and men. Menorrhagia or severe menstrual bleeding (HMB) is the most common symptom of women with bleeding disorders. HMB is defined as bleeding that lasts for more than seven days or as the loss of more than 80 mL of blood per menstrual cycle. The menstrual blood loss can be quantified by the use of a pictorial bleeding assessement chart (PBAC). Samples and methods: In 195 women with menorrhagia and in 45 controls menstrual blood loss was quantified using pictorial blood assesment charts (PBAC) and results were compared. Results: In 169 of 195 women (86%) a bleeding disorder could be detected. In those with a bleeding disorder, the distribution was as followed: 62% had a von Willebrand disease, 14,4% had a factor-VII-deficiency (F7D), 5% had a factor-XIII-deficiency (F13D) and the remaining 18,6% had other beedling disorders (e. g. hypofibrinogenaemia and other mild factor deficiencies). The median PBAC-Score of all patients was 268 (range: 10–4212). In our controi group of 45 women the median PBAC-Score was 46,5 (3- 137).ROC-Analysation shows that the PBAC (AUC=0.977) is much more useful than the number of bleeding days (AUC=0.855) in order to distingish controls from patients suffering from menorrhagia due to a coagulation disorder. We found that the best cutoff for the PBAC is 100 with an sensitifity of 88% and a specifity of 97%. Discussion: Attempts to measure the quantity of menstrual blood loss can be useful in clinic practice. One study found that variables predicting a blood loss higher than 80ml per menses were clots greater than one inch, low ferritin levels, or changing a pad or tampon more than hourly (flooding). A prospective method of quantifying menstrual blood loss includes the use of a pictorial bleeding assessement calendar (PBAC). We are of the opinion, that we would have detected more bleeding disorder also in the patients, where we did not find any diagnosis until now, if we would have controlled them more than one time during the cycle period. Conclusions: Women with hyermenorrhagia frequently suffer from a bleeding disorder, in 86% of our patients an abnormal coagulation was found. The PBAC-Score is an easy tool to quantify menstrual blood loss in women. In our study a PBAC-Score above 100 was suspicious of having a bleeding disorder. Disclosures: No relevant conflicts of interest to declare.

Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates

2019 ◽  
Vol 11 (493) ◽  
pp. eaav7325 ◽  
Author(s):  
Michela Milani ◽  
Andrea Annoni ◽  
Federica Moalli ◽  
Tongyao Liu ◽  
Daniela Cesana ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Nonhuman Primates ◽  
Surface Engineering ◽  
Coagulation Factor ◽  
Lentiviral Vectors ◽  
Factor Ix ◽  
Coagulation Disorder ◽  
Viral Immunity ◽  
Immune Sensing

Liver-directed gene therapy for the coagulation disorder hemophilia showed safe and effective results in clinical trials using adeno-associated viral vectors to replace a functional coagulation factor, although some unmet needs remain. Lentiviral vectors (LVs) may address some of these hurdles because of their potential for stable expression and the low prevalence of preexisting viral immunity in humans. However, systemic LV administration to hemophilic dogs was associated to mild acute toxicity and low efficacy at the administered doses. Here, exploiting intravital microscopy and LV surface engineering, we report a major role of the human phagocytosis inhibitor CD47, incorporated into LV cell membrane, in protecting LVs from uptake by professional phagocytes and innate immune sensing, thus favoring biodistribution to hepatocytes after systemic administration. By enforcing high CD47 surface content, we generated phagocytosis-shielded LVs which, upon intravenous administration to nonhuman primates, showed selective liver and spleen targeting and enhanced hepatocyte gene transfer compared to parental LV, reaching supraphysiological activity of human coagulation factor IX, the protein encoded by the transgene, without signs of toxicity or clonal expansion of transduced cells.

scholarly journals Viral vector platforms within the gene therapy landscape

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jote T. Bulcha ◽  
Yi Wang ◽  
Hong Ma ◽  
Phillip W. L. Tai ◽  
Guangping Gao
Keyword(s):  
Gene Therapy ◽  
Human Disease ◽  
Viral Vectors ◽  
Viral Vector ◽  
Treatment Options ◽  
Full Potential ◽  
Cancer Therapies ◽  
The Past ◽  
Monogenic Diseases ◽  
Therapy Field

AbstractThroughout its 40-year history, the field of gene therapy has been marked by many transitions. It has seen great strides in combating human disease, has given hope to patients and families with limited treatment options, but has also been subject to many setbacks. Treatment of patients with this class of investigational drugs has resulted in severe adverse effects and, even in rare cases, death. At the heart of this dichotomous field are the viral-based vectors, the delivery vehicles that have allowed researchers and clinicians to develop powerful drug platforms, and have radically changed the face of medicine. Within the past 5 years, the gene therapy field has seen a wave of drugs based on viral vectors that have gained regulatory approval that come in a variety of designs and purposes. These modalities range from vector-based cancer therapies, to treating monogenic diseases with life-altering outcomes. At present, the three key vector strategies are based on adenoviruses, adeno-associated viruses, and lentiviruses. They have led the way in preclinical and clinical successes in the past two decades. However, despite these successes, many challenges still limit these approaches from attaining their full potential. To review the viral vector-based gene therapy landscape, we focus on these three highly regarded vector platforms and describe mechanisms of action and their roles in treating human disease.

Sign in / Sign up

Export Citation Format

Share Document