Gene therapy, its limitations and risks in hemophilia
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Niloofar torkzadeh,1,* Mozhgan shirazi,2
- Introduction: Hemophilia is a representative genetic disease with spontaneous bleeding caused by a loss of gene function related to the intrinsic, extrinsic, and common coagulation pathway. Gene therapy provides a potential phenotypic cure for hemophilia yet the cost of this novel treatment is high, tempering enthusiasm and raising questions regarding cost us benefit. Gene replacement therapies provide safe, durable, and stable transgene expression while avoiding the challenges of clotting factor replacement therapies in patients with hemophilia
- Methods: We reviewed about 22 articles were conducted from 2016 to 2022 in the world and Iran. We searched some key words such as Gene therapy, hemophilia, AAV vectors, hepatotoxicity in sciencedirect, Elsevier, PubMed and SID.
- Results: Our results showed that a fundamental treatment has yet been developed and hemophilia A and B are among the most prominent target for gene therapy. The most commonly used treatment for hemophilia is prophylaxis, wherein deficient clotting factor are supplemented depending on the type of hemophilia. A deno_associated virus (AAV) gene therapy has been clinically tested and has demon stated efficacy in restoring deficient clotting factors. Gene therapy targeting hemophilia involves intravenous administration of the F8 transgene within a viral capsid. Intravenous administration lead to preferential targeting of the transgene to the hepatocyte because of the architecture of the livers capillaries. Once the host cell identifies the AAV capsid through its glycosylated cell surface receptors, the virus is internalized via clathrin mediated endocytosis and transported in the cytosol via the cytoskeletal network. A major limitation of the AAV based gene therapy is episomal AAV genomes are not replicated during cell division. Important point to consider when using this approach are the potential loss of factor expression and the consequences of liver growth and dilution of transduced hepatocytes in younger patients. Unfortunately, repeat administration is contraindicated because after the first dose, a humoral immune response is generated against the AAV capsid proteins. It is possible, however, for the raav vector to integrate into animal genomes, which might alleviate the dilution effect. It is important to consider the potential for the development of genotoxicity, which, although rare, can occur. Difficulties removing cellular and viral impurities from raav particles as well as empty AAV capsids, lack of stander dilation, and inherent batch to batch variation in vector potency affect production cost. The availability of convincing evidence for long term expression of transgenic FV Ш and F Іҳ at therapeutic levels, resulting in amelioration of the bleeding diathesis following AAV.
- Conclusion: According to the results, mediated gene transfer is an important step toward development of curative gene therapy. Several obstacles still remain, but the field is evolving at a rapid pace, raising the prospects of eventual license of gene therapy for the hemophilia. Such a product would change the treatment paradigm for patients with severe hemophilia and facilitate the development of gene therapy for other monogenetic disorders, particular those with limited or non-existed treatment options.
- Keywords: Gene therapy, hemophilia, AAV vectors, hepatotoxicity, limitations
