Hemophilia A is characterized by a lack of clotting activity in factor VIII, which causes excessive bleeding after injuries, teeth extractions, or surgery. The frequency and age of diagnosis also relate to the degree of factor VIII clotting activity. Mild hemophilia A patients never experience spontaneous bleeding episodes but may undergo abnormal bleeding during surgery or teeth extractions and postoperative treatment. Such hemorrhage may still occur despite recombinant factor replacement, leading to clinical problems. Therefore, gene therapy and its types, including introducing a new functional gene and gene editing, are necessary to treat, cure, and prevent hemophilia.

Causes of Hemophilia:

Platelets in the blood usually form a clot to stop bleeding; however, when clotting factors are lacking or low in levels, hemophilia develops. The primary risk factor of hemophilia is its presence in the family, and it is more common in men than in women. Hemophilia can be congenital or acquired.

Gene Therapy and Its Types:

Gene therapy, which involves using genetic material (a gene) to treat, cure, and prevent health conditions, comes in two types in treating hemophilia. The first type introduces a new functional gene, either normal or enhanced, into the body to create proteins that function correctly. The second type, gene editing, corrects the mutation by altering the gene. Gene editing has been tested in humans by removing and editing some cells from a person's body before injecting the modified cells back into the body.

Gene Therapy in Hemophilia:

In gene therapy for hemophilia, the most sophisticated clinical trials use a specific type of carrier called a vector, which delivers the gene therapy to the liver cells through the bloodstream. The adeno-associated virus (AAV) vector is the most common. Therefore, the aim in gene therapy is to transfer a therapeutic or functional form of the factor VIII or IX gene into the body to stimulate the target cells into creating the functioning factor VIII or IX. However, oral delivery of DNA in tablet or syrup form is not possible, as it must be safeguarded when supplied through injection or drip into a vein to avoid damage.

Overall, gene therapy for hemophilia has shown remarkable improvements in treating and preventing the disease. While some challenges exist, such as cost, development in highly developed countries has made great strides. The technology will continue to advance in the future, and gene therapy will become more accessible to people worldwide.

The adeno-associated virus (AAV) has been proven to be highly effective in delivering novel factor VIII or IX genes to animals and humans. These viruses carry a protective shell, or capsid, which safeguards the DNA while directing the virus to specific bodily regions. Since the production of factors VIII and IX occurs in the liver, AAV vectors are designed to target liver cells for hemophilia gene therapy.

AAV is a small virus (25-nm) that packages a linear single-stranded DNA genome, belonging to the Parvoviridaefamily, and placed in the Dependovirusgenus. This virus has a unique life cycle and the ability to infect both dividing and non-dividing cells with persistent expression, making it an attractive vector. Moreover, wild-type AAV has no apparent pathogenicity, which is yet another advantageous feature. Gene transfer studies and clinical trials using AAV have shown significant progress and noteworthy safety levels, respectively.

Recombinant AAV (rAAV) vectors are constructed to address concerns about potential effects of Rep on the expression of cellular genes, due to the small size of the AAV genome. These vectors do not encode Rep and lack the cis-active IEE, which is necessary for frequent site-specific integration. The ITRs are kept because they are the cis signals required for packaging, allowing current rAAV vectors to persist primarily as extrachromosomal elements.

Studies of gene therapy for hemophilia using AAV have been ongoing for more than 20 years. Early clinical experiments were unsuccessful but shed light on technical issues that needed resolution. Recent clinical trials using AAV vectors have only included a few individuals and have explored dosages and functional factor variants such as the naturally occurring factor IX Padua variant.

The AAV vector trials for hemophilia A and B were designed to assess long-term effects noticed 12 months after the injection. The most successful trials showed that most participants with severe hemophilia experienced an increase in factor activity levels to the mild hemophilia range (5-40%), and some even increased to the normal range (more than 40%). Furthermore, most participants could stop taking prophylaxis, and nearly all experienced few to no bleeds in the last 12 months.

Possible side effects need consideration.

Individuals with haemophilia who undergo treatment may experience various side effects. These side effects include exhaustion, fatigue, reduced energy levels, anaemia caused by low counts of red blood cells, and pain in the back.

To support gene therapy for haemophilia, several researchers have conducted studies and have published their findings. Berntorp et al. (1995), for instance, highlighted modern treatments that can be used to manage haemophilia. Murphy and High (2008) also discussed gene therapy as a promising intervention for haemophilia, while Daya and Berns (2008) evaluated the use of adeno-associated virus vectors in gene therapy. Furthermore, Perrin et al. (2019) provided an update on clinical gene therapy for haemophilia, which could be beneficial in managing the condition.