Name: Connor ThompsonCourse: Biomedical ScienceStudent ID: 16031137Word count: Genetherapy for haemophiliacs – will it ever be a treatment of choice? Introduction Haemophilia is a geneticallyinherited disease caused by low levels of clotting factor circulating in theblood. There are two forms of haemophilia with two different causes, the first,an absence of clotting factor VIII for haemophilia A, and second, an absence ofclotting factor IX for haemophilia B.

For many years, conventional treatmentshave been used to combat the effects of the disease, mainly through intravenousinjection of concentrated forms of the missing clotting factors. However, asresearch continues into gene therapy, it is becoming a more viable option of treatmentfor haemophiliacs. Haemophilia – The basics Haemophilia is a disease thataffects the bloods ability to clot, usually affecting males due to the inheritednature of the disease and can be sorted into two categories, A and B, with eachbeing caused by a lack of different coagulation factors. Haemophilia A iscaused by low functional levels of blood coagulation factor VIII in plasma,caused by mutations in the coagulation factor VIII gene, it affects 1 in 5,000male births, making it the most common blood disorder. On the other hand,haemophilia B also known as Christmas disease, is caused by the lack ordeficiency of coagulation factor IX, another clotting factor needed foractivation of the coagulation cascade.

 With both forms, there can be a varietyin the severity of the disease measured by the concentration of each coagulationfactor present in the blood, these have been highlighted in Fig.1. A severecase is identified by a FVII/FIX concentration of <1 IU/dl, moderate 1 – 5IU/dl and a mild case being 5 – 30 IU/dl.

With the differing levels of severitycome different symptoms and problems, in mild cases excess bleeding may onlyoccur after trauma, however in the more severe cases recurrent spontaneousjoint and muscle bleeds occur. Fig.1. Degree of haemophilia IU/dl Mild <1 Moderate 1-5 Severe 5-30  Both forms of haemophilia are x –linked chromosomal recessive with each of the genes being close together on thelong arm of the x chromosome. Due to the inherited nature on the x chromosome,the disease is much more prevalent in males due to males only containing one xchromosome, compared to the two of the females.

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 If the disease isn’t inherited,it can be caused by genetic mutation occurring during the embryonic stage oflife with a third of haemophilia B cases being caused by such mutations. Theform of mutation can vary with deletions accounting for 5 percent of cases, withhalf of the more severe forms of the disease being brought about due ‘flip’inversions of base pairs. Conventional therapy Due to the cause of each form ofhaemophilia being a lack of different coagulation factors, different forms oftreatment are necessary to alleviate the symptoms of each. One such form oftherapy for haemophilia A is the use of recombinant FVIII (rFVIII), these areprepared using biotechnological procedures using animal cell cultures. Anotherform of treatment is FVIII concentrates, or prophylaxis if the case is moresevere, this involves the injection of FVIII concentrate that have been formedfrom large pools of plasma.

Such concentrates contain large amounts of highlypurified FVII which are able to activate the coagulation cascade whennecessary, thus allowing blood clots to form. As with Haemophilia A,recombinant techniques are also used to produce recombinant FIX as a means of treatmentfor Haemophilia B. Although similar techniques are used, rFIX is produced by usinga chromatographic technique. While there being no difference in the effects of plasmaderived FVIII concentrates and rFVIII, there is a 30% reduced recovery rate inrFIX when compared to its plasma derived alternative (Franchini et al., 2013).This therefore means that in order to achieve a similar blood plasma level ofFIX when rFIX treatment is used, larger doses are necessary to meet the levels thatplasma derived FIX achieve.  Gene therapy – How it is used to combat haemophilia The concept of gene therapy hasbeen around since the 1970’s, with unsuccessful attempts at implementing genetherapy to treat beta-thalassemia.

Since then gene therapy has been the goldstandard of treatment that researchers aspire to perfect, due to not having tocontinue with current therapy anymore. Gene therapy replaces a mutated genethat causes disease using modified viral vectors, replacing the gene encodingfor viruses with the therapeutic gene and if successfully transferred can restorenormal levels of clotting factor in the blood. In terms of haemophilia A and B,genetic mutations lead to an absence of FVIII and FIX respectively, with eachof these being necessary in the process of coagulation, excess bleeding occurs asblood clots are not able to form.  Although gene therapy treatmentfor haemophilia B has been trialled for the past few years, it has been moredifficult to do so for haemophilia A due to the poor expression profile ofFVIII and the limited size of kb that vectors can express.

Having said this, therehas been recent success with a clinical study increasing FVIII concentration tonormal levels in six out of seven patients for a year after treatment, using avector that encodes for the AAV5-hFVIII-SQ (deleted human FVIII gene) (Rangarajanet al., 2017).    Gene therapy compared to conventional treatment In terms of determining whethergene therapy will become the treatment of choice to treat haemophilia whencompared to the conventional treatments already in practice, it is essential tocompare the advantages that each of the treatments have. Not only this butnegative consequences need to be taken into consideration.  Due to the nature of prophylaxis,constant therapy is required as a means of up keeping blood clotting factorconcentration.

This is highlighted by the fact that in severe cases after administrationof either FVIII or FIX patients only tend to show an increase of one percent interms of their IU/dl levels. However, prophylaxis of clotting factorconcentrates rather than on demand therapy has been proven to be a bettertreatment in terms of reduced joint bleeds and clinical scores at equal costs inyoung people that have a more severe form of haemophilia (Fischer et al., 2002). One key advantage of successfulgene therapy is the continuous expression of clotting factor that is present ina non-haemophilia sufferer, this will mean the elimination of spontaneousbleeding and micro-haemorrhages. Due to the nature of gene therapy, prophylaxiswill no longer be necessary if successful, therefore being a less invasive formof treatment and needing a reduced number of patient contact hours, if genetransfer is successful.  Future of gene therapy With success shown in smallercohorts it is now necessary to expand the clinical trials to determine thesuccesses of gene therapy treatment in the wider population, this willhighlight how viable of a treatment gene therapy is for haemophilia.

In thefuture it will be imperative to continue research into gene therapy, with moresuccessful trials proving that it is the superior form of treatment whencompared to conventional prophylaxis, thus gene therapy will be the treatmentof choice. Conclusion   References Fischer, K., Van der Bom, J.,Molho, P., Negrier, C., Mauser-Bunschoten, E.

, Roosendaal, G., De Kleijn, P.,Grobbee, D. and Van Den Berg, H. (2002) ‘Prophylactic versus on-demandtreatment strategies for severe haemophilia: a comparison of costs andlong-term outcome’. Haemophilia, 8(6) pp.

745-752. Franchini, M., Frattini,Crestani, Sissa and Bonfanti (2013) ‘Treatment of hemophilia B: focus onrecombinant factor IX’. Biologics: Targets and Therapy, p.33. Rangarajan, S., Walsh, L.

,Lester, W., Perry, D., Madan, B.

, Laffan, M., Yu, H., Vettermann, C.

, Pierce,G., Wong, W. and Pasi, K. (2017) ‘AAV5–Factor VIII Gene Transfer in SevereHemophilia A’.

New England Journal of Medicine, 377(26) pp.2519-2530.