Name: caused by low functional levels of blood

Name: Connor Thompson

Course: Biomedical Science

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Student ID: 16031137

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therapy for haemophiliacs – will it ever be a treatment of choice?




Haemophilia is a genetically
inherited disease caused by low levels of clotting factor circulating in the
blood. 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 of
clotting factor IX for haemophilia B. For many years, conventional treatments
have been used to combat the effects of the disease, mainly through intravenous
injection of concentrated forms of the missing clotting factors. However, as
research continues into gene therapy, it is becoming a more viable option of treatment
for haemophiliacs.


Haemophilia – The basics


Haemophilia is a disease that
affects the bloods ability to clot, usually affecting males due to the inherited
nature of the disease and can be sorted into two categories, A and B, with each
being caused by a lack of different coagulation factors. Haemophilia A is
caused by low functional levels of blood coagulation factor VIII in plasma,
caused by mutations in the coagulation factor VIII gene, it affects 1 in 5,000
male births, making it the most common blood disorder. On the other hand,
haemophilia B also known as Christmas disease, is caused by the lack or
deficiency of coagulation factor IX, another clotting factor needed for
activation of the coagulation cascade.


With both forms, there can be a variety
in the severity of the disease measured by the concentration of each coagulation
factor present in the blood, these have been highlighted in Fig.1. A severe
case is identified by a FVII/FIX concentration of <1 IU/dl, moderate 1 – 5 IU/dl and a mild case being 5 – 30 IU/dl. With the differing levels of severity come different symptoms and problems, in mild cases excess bleeding may only occur after trauma, however in the more severe cases recurrent spontaneous joint and muscle bleeds occur.



Degree of haemophilia



<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 the long 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 x chromosome, compared to the two of the females.


If the disease isn’t inherited,
it can be caused by genetic mutation occurring during the embryonic stage of
life with a third of haemophilia B cases being caused by such mutations. The
form of mutation can vary with deletions accounting for 5 percent of cases, with
half 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 of
haemophilia being a lack of different coagulation factors, different forms of
treatment are necessary to alleviate the symptoms of each. One such form of
therapy for haemophilia A is the use of recombinant FVIII (rFVIII), these are
prepared using biotechnological procedures using animal cell cultures. Another
form of treatment is FVIII concentrates, or prophylaxis if the case is more
severe, this involves the injection of FVIII concentrate that have been formed
from large pools of plasma. Such concentrates contain large amounts of highly
purified FVII which are able to activate the coagulation cascade when
necessary, thus allowing blood clots to form.


As with Haemophilia A,
recombinant techniques are also used to produce recombinant FIX as a means of treatment
for Haemophilia B. Although similar techniques are used, rFIX is produced by using
a chromatographic technique. While there being no difference in the effects of plasma
derived FVIII concentrates and rFVIII, there is a 30% reduced recovery rate in
rFIX when compared to its plasma derived alternative (Franchini et al., 2013).

This therefore means that in order to achieve a similar blood plasma level of
FIX when rFIX treatment is used, larger doses are necessary to meet the levels that
plasma derived FIX achieve.


Gene therapy – How it is used to combat haemophilia


The concept of gene therapy has
been around since the 1970’s, with unsuccessful attempts at implementing gene
therapy to treat beta-thalassemia. Since then gene therapy has been the gold
standard of treatment that researchers aspire to perfect, due to not having to
continue with current therapy anymore. Gene therapy replaces a mutated gene
that causes disease using modified viral vectors, replacing the gene encoding
for viruses with the therapeutic gene and if successfully transferred can restore
normal 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 each
of these being necessary in the process of coagulation, excess bleeding occurs as
blood clots are not able to form.


Although gene therapy treatment
for haemophilia B has been trialled for the past few years, it has been more
difficult to do so for haemophilia A due to the poor expression profile of
FVIII and the limited size of kb that vectors can express. Having said this, there
has been recent success with a clinical study increasing FVIII concentration to
normal levels in six out of seven patients for a year after treatment, using a
vector that encodes for the AAV5-hFVIII-SQ (deleted human FVIII gene) (Rangarajan
et al., 2017).




Gene therapy compared to conventional treatment


In terms of determining whether
gene therapy will become the treatment of choice to treat haemophilia when
compared to the conventional treatments already in practice, it is essential to
compare the advantages that each of the treatments have. Not only this but
negative 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 factor
concentration. This is highlighted by the fact that in severe cases after administration
of either FVIII or FIX patients only tend to show an increase of one percent in
terms of their IU/dl levels. However, prophylaxis of clotting factor
concentrates rather than on demand therapy has been proven to be a better
treatment in terms of reduced joint bleeds and clinical scores at equal costs in
young people that have a more severe form of haemophilia (Fischer et al., 2002).


One key advantage of successful
gene therapy is the continuous expression of clotting factor that is present in
a non-haemophilia sufferer, this will mean the elimination of spontaneous
bleeding and micro-haemorrhages. Due to the nature of gene therapy, prophylaxis
will no longer be necessary if successful, therefore being a less invasive form
of treatment and needing a reduced number of patient contact hours, if gene
transfer is successful.


Future of gene therapy


With success shown in smaller
cohorts it is now necessary to expand the clinical trials to determine the
successes of gene therapy treatment in the wider population, this will
highlight how viable of a treatment gene therapy is for haemophilia. In the
future it will be imperative to continue research into gene therapy, with more
successful trials proving that it is the superior form of treatment when
compared to conventional prophylaxis, thus gene therapy will be the treatment
of choice.








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-demand
treatment strategies for severe haemophilia: a comparison of costs and
long-term outcome’. Haemophilia, 8(6) pp.745-752.


Franchini, M., Frattini,
Crestani, Sissa and Bonfanti (2013) ‘Treatment of hemophilia B: focus on
recombinant 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 Severe
Hemophilia A’. New England Journal of Medicine, 377(26) pp.2519-2530.