BLOOD, HAEMOPHILIA AND GENE THERAPY

Haemophilia A

Haemophilia is an inherited bleeding disorder which causes a mutation in the genes responsible for clotting blood There are two types: the first haemophilia A where the individual has a mutation in the gene that codes for factor VIII, the second haemophilia B where the individual has a mutation in the gene that codes for the IX factor. Mutations in either of these factors lead to similar issues including excessive and potentially fatal bleeding as a result of the blood's inability to clot. For the purpose of this article, I will be focusing solely on an emerging treatment for haemophilia A

Current treatments

Haemophilia A is traditionally treated with an infusion of the factor VIII every 2-3 days, meaning that on average 150 treatments are required every year. This is due to the short half life of factor VIII at an average of only 12 hours before its activity halves, hence the frequent infusions Several methods have been investigated to increase the half life of factor VIII infusions, including Fc fusion technology, which has been found to increase its half life by 1 5X, However, even with such technology patients still have to attend frequent appointments, posing an impractical and potentially expensive problem in their lives.

Gene therapy- the cure for haemophilia A?

A new and exciting gene therapy treatment has been developed to treat and potentially cure haemophilia A I will describe the treatment “valoctocogene roxaparvovec” , its benefits and finally its weaknesses. I will also comment upon potential areas of improvement, including alternative viral vectors and other delivery mechanisms that could instead be used.

Gene therapy is the modification of specific genes responsible for harmful mutations to cure or treat illnesses, via either “in vivo”, inside the body, or “ex vivo”, outside the body, methods “In vivo” gene therapy is when healthy genes from another specimen, which the patient lacks, are delivered to the patient via a genetically modified “vector” and integrate themselves into the recipient's genome “Ex vivo” gene therapy is when a mutated gene is removed from the patient's genome, externally edited to correctly code for the specific protein, before being re-inserted back into the body utilising a genetically modified vector Valoctocogene roxaparvovec is an example of “in vivo” gene therapy. Patients receive a genetically engineered vector containing the gene that codes for factor VIII, which is mutated in those with haemophilia A This is a “one time treatment”, as once the healthy transgene has integrated itself into the patient's genome, in 88% of trial patients, their factor VIII levels were high enough that they were deemed to either have a mild case of the illness or to no longer have it at all.

DR DOLPHIN: THE HUMAN BODY

Use of a viral vector

The vector, sometimes referred to as the “delivery vehicle” of gene therapy, in this particular treatment is an adenosine virus. It is modified so that harmful, viral DNA is removed to prevent the virus from causing illness. The transgene, in this case the gene that codes for factor VIII, is inserted into the genome of the virus The genetically modified virus containing the gene coding for the factor VIII can then be injected into the patient, allowing the virus containing the desired transgene to infect cells and replicate Factor VIII as a result can be correctly transcribed in the body to allow for clotting factors to be produced and prevent excessive bleeding associated with haemophilia

However, a side effect noted in some patients during the trial highlights a key issue in using viral vectors as part of gene therapy treatments. Some patients were found to have elevated liver enzymes as a result of receiving the therapy This implies that although all harmful DNA would have been removed from the adenovirus vector, an immune response was still carried out by the body having recognised the antigens on the surface of the virus and deeming it “harmful” and in need of destruction by the immune system. Evidently, this is problematic as should the body launch an immune response, the viral vector containing the needed transgene would be destroyed ultimately defeating the purpose of the treatment.

While immunosuppressants are often used in gene therapy to weaken the body's immune system such that it no longer attacks the virus, in a chronically ill patient, including those with haemophilia A, this is a risky approach as weakening the immune system also leaves them susceptible to other harmful infections.

An alternate way of avoiding this inflammatory immune response might be to use a different viral vector, perhaps the adenosine associated virus This virus has been found to be less immunogenic than other viral vectors, hence increasing the odds of the virus surviving in the body to successfully deliver the transgene by evading the immune system Other studies have even suggested utilising different methods of transgene delivery altogether These include sonoporation, whereby ultrasound waves are utilised to make cell membranes more permeable and furthermore to guide a “micro bubble” containing the transgene to the target cells, or electroporation, utilising an electric field to create small pores in the cell’s membrane again to allow the transgene to enter the cell. These “physical” delivery methods are arguably better than using viral vectors as although they come with their own risks, They avoid the issue of an immune response as discussed above

DR DOLPHIN: THE HUMAN BODY