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Gene Therapy in Hemophilia: Recent Advances.

ABSTRACT: Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed.

SUBMITTER: Rodriguez-Merchan EC

PROVIDER: S-EPMC8306493 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Progress in hemophilia therapy has been remarkable in the first 20 years of the third millennium, but the innovation began with the description the fractionation of plasma in 1946. The first concentrates followed the discovery of FVIII in the cryoprecipitate of frozen plasma and FIX in the supernatant in the early 1960s, which led to the initial attempts at replacement therapy. Unfortunately, the lack of screening methods for viral pathogens resulted in people with hemophilia (PWH) receiving concentrates contaminated by hepatitis A virus, hepatitis C virus, and human immunodeficiency virus, as these concentrates were made from large industrial pools of plasma derived from thousands of donors. Fortunately, by 1985, viral screening methods and proper virucidal techniques were developed that made concentrates safe. Increasingly pure products followed the introduction of chromatography steps with monoclonal antibodies in the production process. The problem of immunogenicity of exogenously administered concentrates has not yet had a complete solution. The development of alloantibodies against FVIII in about 25-35% of PWH is the most serious adverse effect of replacement therapy. The next major advance followed the cloning of the F8 gene and later the F9 genes, which paved the way to produce concentrates of factors obtained by the recombinant DNA technology. The injected FVIII and FIX molecules had a relatively short circulating half-life in the plasma of people with hemophilia A and B, approximately 12 and 18 hours, respectively. The ability to prolong the plasma half-life and extend the interval between injections followed the application of methods to conjugate the factor molecule with the fragment crystallizable of IgG1 or albumin or by adding polyethylene glycol, which has led to an increase in the half-life of concentrates, especially for rFIX. The next frontier in hemophilia therapy is the application of durable and potentially curative therapies such as with gene addition therapy. Experiments in hemophilia B have demonstrated durable responses. Unfortunately, the results with gene therapy for hemophilia A have not been as remarkable and the durability must still be demonstrated. Nonetheless, the long-term safety, predictability, durability, and efficacy of gene therapy for hemophilia A and B remain an open question. At present, only healthy adult PWH have been enrolled in gene therapy clinical trials. The application of gene therapy to children and those with pre-existing antibodies against the delivery vector must also be studied before this therapy becomes widespread.

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Gene Therapy in Hemophilia: Recent Advances.

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