Hemophilia is a Mendelian disease (which is inherited by the mutation of a single gene) on the X chromosome, the disease is transmitted as a sex-linked character, occurs mainly in males.
It is a recessive genetic disease that prevents the proper coagulation of blood. As a result, the wounds of those affected bleed for a longer period of time, leading to hemorrhages both externally and internally.
The mechanism of «coagulation» responsible for the formation of fibrin (produces the definitive clot of lax aggregate of platelets) involves a series of reactions in «cascade», accepting a numerical system for the different coagulating factors.
There are several types:
Hemophilia A: when there is a deficiency of coagulation factor VIII (glycoprotein), 1 person per 10000 males, plays a fundamental role in the transformation of prothrombin into thrombin intrinsic pathway.
Hemophilia B: deficit in coagulation factor IX (beta antihemophilic factor), 1 person for every 32,000 males, stimulates factor X.
Hemophilia C: deficiency in the clotting agent XI (plasma thromboplastin), 1 person per 15,000, stimulates factor IX.
There is currently no curative treatment available (with the exception of a liver transplant), the hemorrhagic tendency can be corrected by intravenously administering the missing coagulation factor, factor VIII or IX.
In recent years, the development of genetic engineering has made it possible to start a new era in the treatment of the disease. It consists in the introduction of genes in the patient’s determined cells that are able to combine with the existing genetic material, providing the missing information to make the deficient protein that causes the disease.
Researchers at Children’s Hospital of Philadelphia (USA) seem to have found a way to do it. The study published in the journal «The New England Journal of Medicine» (December 7, 2017) presented by Dr. Lindsey A. George, assistant physician of the Hematology Division principal investigator of the trial: 10 patients treated in the study experienced a sustained clinical benefit after a single infusion, in this case adults with hemophilia B can synthesize coagulation factor IX in a safe way. The study carried out is of the so-called «phase I / II».
They used the «factor IX-Padua«, a coagulation factor discovered in 2009 and produced naturally by members of a family in the Italian city of Padua, which has a coagulation capacity up to 10 times higher than factor IX «Normal», the goal of the new therapy was to «introduce» the gene that codes for «factor IX-Padua» in patients with hemophilia B so that they could synthesize it by themselves. The authors used as a vector an adeno-associated virus (AAV) that carried the gene responsible for the expression. The 10 treated adult males maintained coagulation factor levels close to 33%, enough to eradicate most episodes of bleeding. After the 78 weeks of study, the levels of the coagulation factor remained stable.
In parallel Spark Therapeutics and Pfizer on December 20, 2017 announced the preliminary data of a phase 1/2 clinical trial conducted with a gene therapy for hemophilia B. Published in the «New England Journal of Medicine» on July 25, 2017: led by Dr. Katherine A. High president and director of research and development of Spark Therapeutics and co-author of the article, in this open, non-randomized, multicenter clinical trial, 10 adult male patients receive an infusion of SPK-9001, the annual bleeding rate (TSA) decreased by 97%, after a cumulative follow-up period of 492 weeks of observation factor IX was 34% of normal., they could have the potential to safely maintain the level of coagulant activity.
In July, Pfizer initiated an open-label, multicenter phase III study (NCT03587116) with experimental gene therapy (elaparvovec fidanacogen) to evaluate the efficacy and safety of the current treatment for factor IX replacement.
AAV adeno-associated viruses: viruses similar to those that cause colds, which have a very small genome, the great advantage is that they have the ability to integrate their genome into non-dividing cells, used as a vector to introduce the gene.
Multicenter study: it is carried out in more than one medical institution
Non-randomized study: participants are not randomly assigned.
Open study: both the researcher and the patient know the identity of the drugs used.
Phase I study: first studies involving humans, usually of small dimensions. The way to administer the drug and the highest dose that can be administered without risk is studied.
Phase II study: the effectiveness of the new treatment is monitored, it is observed if any benefit occurs.
Phase III study: they compare safety and effectiveness of the new treatment with the current reference treatment, they are large, they are carried out in several places.
Timothy M.Cox & John Sinclair; «Molecular Biology in Medicine», Ed. Blackwell Science, 1997
• Valder Arruda & Ben J. Samelson-Jones; «Factor IX Padua: From Biochemistry to Gene Therapy»; Blood; 2016
• Lindsey A. George et al.; “Hemophilia B Gene Therapy with a High-Specific-ActivityFactor IX Variant; The New Journal of Medicine”;; December 7, 2017
• Clinical Trial NCT03587116
Clinical Trials. gov; July 2018
FDAAA Trials Tracker; July 2018