Potential future therapies for haemophilia
The haemophilias are disorders that affect the blood clotting system. Roughly 85% of haemophilia sufferers are affected by haemophilia A this translates into roughly 1 in 5000 males. Haemophilia B affects roughly 1 in 30,000 male. Haemophilia is a disease which has been in the spotlight in recent years due to it being an ideal candidate for gene therapy. Some have stated that if gene therapy cannot be implemented with haemophilia it is unlikely to work in other diseases.
Research into a number of future therapies to aid treatment of haemophilia suffers has yielded good results. Certain future treatments such as gene therapy if successful in haemophilia could pave the way for treatment of other diseases.
Gene therapy
Haemophilia has been recognised as a potential candidate for gene therapy. These are just some of the main reasons :
- The various clotting factors involved in the blood coagulation process can be expressed by a wide variety of cell types.
- The disease can also be recreated in numerous animal models, because of this fact extensive research can be conducted, so when human trials of gene therapy occur there is less ambiguity regarding the effect of treatment on humans. It would basically allow for researchers to fine tune the treatment to make it as effective as it can be.
- The effectiveness of the treatment can be easily tested using assays to determine the concentrations of the various factors.
Gene therapy in theory is a process that corrects certain deficiencies in patients by inserting functional DNA copies into cells, so the patient can express a normal protein. In haemophiliacs this would involve inserting functional copies of genes that create the correct forms of factors VIII and IX into the appropriate cells
The uptake of the genes into the cells of haemophilia suffers would occur using a process known as transduction. This process is facilitated by vectors. Vectors are commonly derived from viruses as they are extremely effective at transduction. There are three main types of vectors which could be used, all have advantages and disadvantages associated with them. The three types are:
- Adeno-associated viral vectors: These vectors are DNA based, and integrate extremely well into hosts; however there is a delay of roughly 3-6 week before expression occurs at its maximal potential. Furthermore it is possible for these types of vectors to carry out transduction by themselves without any help.
- Adenoviral vectors: These vectors are also DNA based, a difference with this type of vector is that the DNA does not integrate with the host DNA rather it is left free and operates separately from the host DNA. This in itself is a problem with this vector as it has low integration success and furthermore the DNA does not get replicated during cell division so it would need to be transduced into the replicated cells also.
- Retroviral Vectors: These vectors differ from the others due to them being RNA based. When this vector is inserted into the host’s genome the RNA molecule is used as a template to create double stranded DNA, through a process known as reverse transcription. This process has high integration and transduction rates but suffers from the fact that it can only be utilised during cell division.
Trials using animal models have yielded successful results. These animal models include mice, rabbit and primate models. The success within primate models is especially critical because primates have a high homology with human and thus shows that the treatment could be successfully implemented in human.
Although the prospects for gene therapy look good the treatment is still far off from actually becoming a reality and being used mainstream. Furthermore controversy was generated surrounding gene therapy after the highly publicised death of Jesse Gelsinger who died while receiving gene therapy treatment. He suffered from an immune response to the viral vector.
Immune tolerance therapy
A common problem associated with giving replacement therapy to haemophilia A suffers is that 22-52% of the sufferers will generate FVIII inhibitors, which will prevent replacement FVIII from operating. Immune tolerance therapy has been used successfully to treat this problem and is effective in roughly two thirds of patients but this process is riddled with many complications such as high cost and availability of factors. Kurth et al (2007) evaluated a group of patients using FVIII/Von Willebrand factors (FVIII/VWF) as a replacement in ITI. This form of treatment is carried out over a shorter period of time and improves the effectiveness of immune tolerance therapy. It has been postulated that the VWF component reduces degradation of FVIII.
The patients in this study had severe haemophilia A with high levels of FVIII inhibitors. They had also responded poorly to previous ITI. 72% of patients showed a response to treatment with FVIII/VWF and 32% of patients did not have any success with this form of ITI. This however is just the beginning for utilising FVIII/VWF in ITI treatment (Kurth et al, 2007).
Rituximab
Rituximab is an antibody commonly used to treat patients with non-hodkins lymphoma. Research has also shown that this antibody may be successful in haemophilia patients with high factor inhibitor concentrations. These high inhibitor concentrations prevent them from being treated efficiently using conventional methods. Research into this treatment is still in its early stages and trials are still ongoing.
Final thought
In many poorer countries haemophilia sufferers tend to go undiagnosed and thus many of these sufferers actually die from this condition without ever knowing they had it. The world federation of Haemophilia is trying to change this trend by improving healthcare in these less developed countries so treatment and diagnosis of haemophilia improves (Bolton-Maggs et al,2003). When the haemostasis process had been fully elucidated hopefully diagnosis of this disease will become much easier and with the area of gene therapy sparking interest there is a large probability this could drastically reduce the mortality and morbidity rate associated with these bleeding disorders.
