scholarly journals A Hemophilia Disorder Review: Gene Therapy for Hemophilia B Treatment using rAAV vectors

Bionatura ◽  
2019 ◽  
Vol 02 (Bionatura Conference Serie) ◽  
Author(s):  
Abad Gallardo Claudia Sofía ◽  
Merchán Muñoz Brian David
Keyword(s):  
Gene Therapy ◽  
Blood Clotting ◽  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Adeno Associated Virus ◽  
Long Term Effect ◽  
Blood Clotting Factor

Hemophilia is an X-linked recessive disorder characterized by the deficiency in one protein essential for blood coagulation. There are two main types of variants of this disease; hemophilia A (HA) which is related with blood clotting factor VIII (FVIII) deficiency and hemophilia B (HB) which is related with factor IX (FIX) deficiency. Nowadays, there are several options to treat this disorder, however, the most efficient is gene therapy since it has a long-term effect, and contrasts with traditional methods. This review is focused on hemophilia B treatment because FIX is a smaller protein than FVIII (<1kb), and thereby is easier to study. Within gene therapy, methods which use recombinant adeno-associated virus (rAAV) vectors are the best alternative to treat HB since they are safe and reliable. Moreover, rAAV vectors have the advantage of having a low inflammatory potential, a non-pathogenic status, plus the potential for long-term expression of the transferred gene. However, some patients showed an immune response to the capsids of the vectors before treatment. Hence, possible solutions were needed; one of them being the use of anti-antibodies. Finally, clinical trials results showed that under the use of the optimized codon hFIXco and serotype 8 the levels of expression were persistent, demonstrating the potential of gene therapy for hemophilia B treatment.

Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2670-2676 ◽  
Author(s):  
Jane D. Mount ◽  
Roland W. Herzog ◽  
D. Michael Tillson ◽  
Susan A. Goodman ◽  
Nancy Robinson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Large Animal Model ◽  
Null Mutation ◽  
Large Animal ◽  
Adeno Associated Virus ◽  
Increased Risk

Abstract Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (FIX). Using adeno-associated virus (AAV)–mediated, liver-directed gene therapy, we achieved long-term (&gt; 17 months) substantial correction of canine hemophilia B in 3 of 4 animals, including 2 dogs with an FIX null mutation. This was accomplished with a comparatively low dose of 1 × 1012 vector genomes/kg. Canine FIX (cFIX) levels rose to 5% to 12% of normal, high enough to result in nearly complete phenotypic correction of the disease. Activated clotting times and whole blood clotting times were normalized, activated partial thromboplastin times were substantially reduced, and anti-cFIX was not detected. The fourth animal, also a null mutation dog, showed transient expression (4 weeks), but subsequently developed neutralizing anti-cFIX (inhibitor). Previous work in the canine null mutation model has invariably resulted in inhibitor formation following treatment by either gene or protein replacement therapies. This study demonstrates that hepatic AAV gene transfer can result in sustained therapeutic expression in a large animal model characterized by increased risk of a neutralizing anti-FIX response.

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 Association of Haemophilia with Down Syndrome

2016 ◽  
Vol 36 (1) ◽  
pp. 75-77
Author(s):  
Gursharan Singh Narang ◽  
Tarsem Singh ◽  
Anubha Sharma ◽  
Supriya Malik ◽  
Amandeep Kaur
Keyword(s):  
Down Syndrome ◽  
Blood Clotting ◽  
Down's Syndrome ◽  
Down’S Syndrome ◽  
Bleeding Disorder ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Blood Clotting Factor

Hemophilia B is a hereditary bleeding disorder caused by a lack of blood clotting factor IX. Without enough factor IX, the blood cannot clot properly to control bleeding. Hemophilia B presenting in association with Down’s syndrome is quite rare. We report a case of a one month old child who presented to us with continuous unexplained bleeding.J Nepal Paediatr Soc 2016;36(1):75-77.

Prospects for the use of prolonged concentrates of blood clotting factor IX in the treatment of hemophilia B

2021 ◽  
Vol 7 (4) ◽  
pp. 56-61
Author(s):  
V. N. Konstantinova ◽  
T. A. Andreeva ◽  
A. V. Kim
Keyword(s):  
Blood Clotting ◽  
Patient Adherence ◽  
Coagulation Factor ◽  
Hereditary Disease ◽  
Factor Ix ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Clotting System ◽  
Molecular Abnormalities ◽  
Blood Clotting Factor

Hemophilia B is a hereditary disease of the blood clotting system caused by a deficiency or molecular abnormalities of blood clotting factor IX. The main method of treatment is intravenous administration of coagulation factor IX concentrates. To optimize treatment and increase patient adherence to therapy, concentrates with a prolonged half-life have been developed.

Synthesis of a glycopeptide related to blood clotting factor IX

Peptides 1992 ◽  
1993 ◽  
pp. 361-362
Author(s):  
B. Lüning ◽  
T. Norberg ◽  
J. Tejbrant
Keyword(s):  
Blood Clotting ◽  
Factor Ix ◽  
Clotting Factor ◽  
Blood Clotting Factor

Gold nano-urchin integrated label-free amperometric aptasensing human blood clotting factor IX: A prognosticative approach for “Royal disease”

2019 ◽  
Vol 131 ◽  
pp. 128-135 ◽  
Author(s):  
Iswary Letchumanan ◽  
Subash C.B. Gopinath ◽  
M.K. Md Arshad ◽  
Periasamy Anbu ◽  
Thangavel Lakshmipriya
Keyword(s):  
Human Blood ◽  
Blood Clotting ◽  
Factor Ix ◽  
Clotting Factor ◽  
Label Free ◽  
Blood Clotting Factor

A case of rare inhibitory coagulopathy - acquired hemophilia A

2010 ◽  
Vol 94 (10) ◽  
pp. 775-779
Author(s):  
V. I. Ershov ◽  
Dar’ya A. Budanova ◽  
I. Yu. Gadaev ◽  
O. V. Bochkarnikova ◽  
I. Ya. Sokolova ◽  
...  
Keyword(s):  
Rare Disease ◽  
Blood Clotting ◽  
Hemophilia A ◽  
Coagulation System ◽  
Clotting Factor ◽  
Factor X ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Hemostatic Therapy ◽  
Blood Clotting Factor

Inhibitory coagulopathy is a rare variant of hemorrhagic syndrome. Acquired hemophilia A is caused by the formation of inhibitors (antibodies) to Factor VIII of the blood coagulation system leading to impaired activation of the key stage of blood clotting (factor X) and development of hemorrhagic syndrome of different severity. Acquired hemophilia A is a rare disease with an incidence of 1.38-1.48 per 1 million population per year. We report a case off severe idiopathic acquired hemophilia A in a 53 year-old woman manifest as skin hemorrhages, subcutaneous and intramuscular hematomas. Hemostatic therapy described in the article resulted in the elimination of hemorrhagic syndrome and complete remission. This case represents a rare disease the knowledge of which can be useful for preventing the development of debilitating complications, and sometimes saving the patient’s life.

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