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Introduction
of Hemophilia and Gene
Therapy
In the field of medical science, a
lot of revolution has been observed over the years, and great progress has been
made in so many ways. The research and knowledge along with the revolution of
technology, medical science has done a great job. There were so many diseases,
which could not be cured in the past, but medical sciences kept working hard to
find medicines and treatments for those diseases. This is the kind of
contribution made by medical science. However, the focus in this paper is not
on the overall role and contribution of medical science, rather focus will be
given to Haemophilia and its gene therapy. In this paper, a brief discussion
will be made to discuss the disease of Haemophilia, and then the complete focus
will be given to its gene therapy, like how it started, its success or failure
along with other important elements
Before looking at gene therapy for
Haemophilia, it is vital to understand what Haemophilia is, and how it affects
a human being. It is actually a disorder, which happens due to genetic blood
clotting. It is important to understand what happens with the patients of
Haemophilia. If a patient is diagnosed with Haemophilia, and he/she was
injured, where some kind of cut on his/her body, then blood will flow from that
cut. In a normal and healthy person, this blood will stop automatically in few
minutes, but it does not happen for the patient of Haemophilia, because there
are different reasons in Haemophilia, which do not allow blood to make clots.
It means that bleeding of a Haemophilia patient cannot be stopped, which is a
dangerous thing to happen. There are various essential ingredients needed for
blood clotting, but a patient with Haemophilia does not have that kind of
ingredient, which means that blood clotting is not done properly. One of the
ingredients in this regard is blood proteins, which helps the human body to
make blood clots. It is also important to know that for some patients, the
disorder can be severe, but for many, it is moderate or mild.
Types of Hemophilia and Gene Therapy
The
haemostasis relates to the coagulation factors which will have platelet
biology. According to the research, haemostasis is a kind of bleeding disorder
in human being. An example of haemostasis can be recognized as haemophilia. Haemostasis
causes issues in the bleeding system of the human being. It causes to bleed
into the joints and muscles of the patient which can be dangerous in some
cases. The haemophilia A is represented as haemophilia VII as it relates to the
deficiency of coagulation factor in the human being. While such a situation
also causes a disorder of X-linked recessive disorder.
Moreover,
it relates to the haemophilia IX and B. According
to the recent surveys, it is concluded that haem A chances are relatively
higher in males as compared to females. Findings conclude males will have
haemophilia around 1 in 10,000. However, males will have relatively lower chances
of haem B as found by the research. An expectation of haem B is around 1 of
50,000. Haemophilia is curable but in very high budgets. A person seeking for
the current treatment of haemophilia A or B will have to purchase the treatment
option of recombinant proteins. The haemophilia is made available for around
30% of the total haemophilia patients because of its highly expensive treatment
systems. According to the opinion of some researchers, Haemophilia is inconvenient
and immunogenic for the patients because of limited treatment opportunities
available in the healthcare centres, hospitals, and private clinics.
Following medical research findings, there are
two types of Haemophilia which include the following:
The
Haemophilia is a kind of deficiency identified by the medical staff in
the clotting factor VIII. This kind of deficiency is recorded as a symptom of
prolonged bleeding from the muscles and joints of the patient in common
conditions. An X-linked recessive trait affects males health and causes to the
inherited disease of Haemophilia A. However, such cases are also
recorded with the cause of spontaneous mutations in the males. Although, this
disease is mainly supported by the genetics of the patients. As an inherited
disease it transfers from a generation to the next generation.
In
the Haemophilia A body starts bleeding because of abnormalities in the clotting
factors. Following the concept of modern health sciences, the human body is
meant to produce clots in order to keep a person save from the bleeding
process. Blood cells join together in the body of a person to create clot for
this purpose. Then consequently a clot developed from the blood cells process
the prevention of blood flowing from muscles and joints. In general, clots in
the muscles and joints support the normal flow of blood while controlling its
abnormal flow such as excessive bleeding. According to the medical sciences, Haemophilia
A is a result of changes in the F8 gene which relates to the mutations of the
F9 gene in the males. Type A is a classic one, and around 80% of Hemophilia
patients do have this type, whereas Type B is not that common, and around 20%
of patients have to deal with it. It is hard to look at any visible symptoms of
the disease unless a person faces severe bleeding due to any injury or medical
treatment
Haemophilia B is another major cause of bleeding in
the patients however it does not entirely relate to the Haemophilia
A. Haemophilia B was first identified by the medical staff in 1952 when a
distinct diseases spread in many areas. Since that time medical researchers are
continuously conducting research work on this health issue to introduce a fully
functional formula for the treatment of 100% success rate. Haemophilia B is
mainly a blood clotting disorder that causes east bruising in the body because
of excessive inherited mutations occurred in the human body with the relation
of factor IX gene. Another major cause behind this Haemophilia B is the
deficiency in the VIII factor of the body resulting in the decrease of factor
IX gene. Haemophilia B is also known as Christmas disease in many
countries. The reason behind this name
is the history of these diseases. Following the literature, Haemophilia B was
first diagnosed in 1952 in a person named Stephen Christmas therefore many
people still relate this disease to the name of its first patient. Somehow,
currently, Haemophilia B has no proper treatment and medicine. Most recommended
medication system in Haemophilia B is related to the control of disease instead
of complete eradication in a patient. Haemophilia B treatment has relatively
higher chances of success in the patients of liver transplants.
Difference
Between Haemophilia A and Haemophilia B
Haemophilia
A and Haemophilia B are typically considered the same because of similarities
in name and outcomes. However, Haemophilia A and Haemophilia B are not all the
same. Both diseases are different from each other even both shares some common
symptoms and causes. The following table represents differences in Haemophilia
A and Haemophilia B based on the research findings from the literature
review.
|
|
Haemophilia A |
Haemophilia B |
|
Deficiencies |
The Haemophilia A is because of the
deficiency of factor VIII (gene 8) in the patients. |
The key reason behind Haemophilia B is a
deficiency of factor IX (gene). |
|
Clotting Factors Time |
The clotting factor timing is also a
major difference between Haemophilia A and Haemophilia B. In Haemophilia A
clotting factor last for relatively less time, therefore, patients of
Haemophilia A have to take injections at least 3 times a week. |
Haemophilia B diseases are not really
critical for the clotting factor therefore patients of Haemophilia B need to
take injections for only 2 times during 18 weeks. |
|
Treatment |
The treatment of Haemophilia A is made
available in very high budgets as it requires prophylaxis injections at least
3 times a week or on a daily basis (in some rare cases). |
Haemophilia B has no significant
treatment yet which could provide a 100% success rate. However, proper gene
therapy and prophylaxis injections are recommended as the treatment of
Haemophilia B. |
The
gene therapy is recommended for the treatment of Haemophilia A and Haemophilia
B. Haemophilia A require gene treatment for at least 104 week duration in
average cases however time may increase or decrease based on the critical
condition of the patient with Haemophilia A disease. Gene therapy success rate
is relatively higher than the Haemophilia B gene therapy success rate.
According to a research total, 71% of patients succeeded to get proper gene
therapy to recover from this disease. However, the total number of patients who
received this gene therapy treatment was around 7. See the following graph
regarding the gene therapy of Haemophilia A.
Gene
therapy is also recommended in Haemophilia B cases. However, there are many
challenges linked with this type of therapy therefore it is recommended after a
complete examination of the patient and capability of the patient to meet the requirements
of gene therapy.
Gene
therapy is not the only recommended therapy for Haemophilia A and Haemophilia
B. The following are also common kind of therapies for Haemophilia A and B.
Replacement
Therapy: in this therapy specific kind of clotting factors are placed in the
veins by the use of the tube. This therapy includes the use of denoted blood.
Bypassing
Agent Treatment therapy: This is a monoclonal antibody treatment for the immune
system.
The
above stated therapies are the most common therapies for Haemophilia A and B
however selection depends upon the health condition of patient.
Source: https://infograph.venngage.com/p/224057/kevin-umana-period6-infographic
First
of all, it will be important to understand Gene Therapy with a simple
explanation. In gene therapy, a modified virus is used so that a new gene is
introduced for the encoding of the blood clotting factors, which are missing in
the patients of Haemophilia. It is vital to mention here that the modified
virus used in gene therapy is not known to produce any kind of disease. There
are two important factors for a gene to produce clotting, which are IX (FIX)
and VIII. It is vital to study gene therapy with relevant elements to get more
understanding of the treatment for the patients of Haemophilia
In
the gene therapy field, the two most researched and studies diseases are Type A
and B of Haemophilia, which shows how important this issue of Haemophilia has
been. This research has been beneficial in a variety of ways to treat patients
having Haemophilia
Figure 2: Comparison of characteristics of haemophilia A and B
The primary objective to go with
gene therapy is to make editing in the sequence of the defective gene so that
the disease phenotype is completed with a reversion. It is vital to mention
here that gene research has not just focused on the replacement or editing of
the defective gene, but the actual focus of the process is to make an addition
in the gene, rather making any replacements. It has been done in this way,
because when gene addition is made, it can do its job effectively, rather in
the replacement process, there are various complexities are involved. So, gene
addition has always been the center of attention. It is also important to know
that disease models associated with animals have been used in the research of
gene transfer. The issue is that sometimes diseases are overrepresented, and if
things could be kept simple, the results can be better in so many ways.
It
is vital to know that gene therapy was first started in 1989, as it was the
time when the first gene therapy trial for humans was approved. The beauty of
gene therapy is that it is not only effective for Hemophilia, but it can deal
with a variety of diseases. It is important to understand in the field of
medical sciences, things are never done at a rapid speed, rather clinical
trials and experiments take a lot of time before their worldwide implementation
is allowed. In the case of gene therapy, the research started in 1989, and
until 2015, the number of clinical trials for gene therapy was 2,335. Out of
these total trials, 67% of trials were undertaken by the United States. The
majority of these gene therapy trials have been conducted for the patients dealing
with the cancer disease. Regardless of so many clinical trials, gene therapy
was not approved to be used worldwide. After extensive phases and trials for so
many years, the first gene therapy in Europe was approved in 2012. It shows
that any medical treatment process or therapy takes a lot of time to get into
the reality of application when it is made sure that the trials are successful
in a majority of numbers, and things are proved with great results
Figure
3
Source: https://genetherapy.isth.org/a-history-of-hemophilia-treatment-factor-replacement-to-gene-therapy
The
number of patients of Haemophilia is increasing with the passage of time, and
around 200,000 persons all around the globe are dealing with Haemophilia. The
issue of this disease is that patients have to face so many issues such as
financial and psychological challenges along with managing this disease in
their daily lives. One of the standard treatments for the patients of
Haemophilia is to do self-infusion in the prescribed amount of factor IX and
VIII. It is not an easy thing to do on a daily basis. The other important issue
for patients is to ensure that they don’t get injured. They have to avoid any
sort of even minor injury, which may lead to bleeding, which is a big challenge
itself. They also have to make sure that their joints are protected from any
kind of damage. It is vital to understand the current state of gene therapy to
look at existing facts and analyze future challenges. The good news for
patients of Haemophilia is that gene therapy has shown a great promise in
treating Haemophilia patients with the use of vectors such as adeno-associated
viral (rAAV), which plays a part in the transduction of factor IX and VIII
The
experimental models associated with animals have also been showing great
progress for gene therapy to have experimented with humans. One of the first
trials with success involved rAAV8-FIX vector’s peripheral infusion was given
in 2008. The 10 patients were part of the trial, and these patients were having
Haemophilia B. When a dose was given to these patients, it was noticed the
relationship of dose with the response, which showed that when the dose was
given in normal amount, the activity of factor IX showed the range from 1.4%,
which went up to the range of 2.9%, but this percentage was higher when the
dose was given in high amount. In one more clinical trial, 9 patients who were
dealing with Haemophilia A were given the dose of single-stranded B domain-deleted
factor VIII (BDD-FVIII). The follow up of these patients was done for around 1
year to see the results. The experiment shows that patients, who were given
high dosage, they demonstrated the activity of vector VIII going above the
range of 50 IU/dL. The other great thing about this trial was that all observed
patients showed a great reduction in the use of factor VIII, and hemostasis was
also very much stabilized
There
was a time when Haemophilia was taken as a disease with debilitating features,
but things have changed a lot in last decade or so due to extensive research in
this field, the disease has been taken to some manageable conditions, and more
improvements are being made with the passage of time. The only issue is that
current options available for the treatment of Haemophilia are not only
expensive, but they are also complex in so many ways. That’s why, a large
portion of people around the world are not able to get access to these
treatment methods, and these treatments cannot be taken to masses for greater
improvements overall. In replacement factors, the development process of
antibodies has also been a complex one, as it has been observed that there are
various complications are associated with the process, and due to these
complications, the annual rate of bleeding has increased in the affected
Haemophilia patients. That’s why; the focus has been given to curative gene
therapy instead of going with replacement factors. Many clinical trials with
the experiments of gene therapy have been able to produce good results, and
these promising results have asked for more trials. The new progress has been
made, but not without developing issues. The issues are not only logistical,
but there are various ethical issues as well. There are no measures to
accurately evaluate the therapeutic outcomes of gene therapy, especially in
pediatric patients. The other issue is setting equitable pricing for the
patients’ medication, so that accessibility is made possible for a larger
portion of people around the globe. If the clinical application is going to be
made possible, then these issues should be resolved as early as possible
The future challenges in the essence
of gene therapy for Haemophilia patients are still to face for years to come,
and this disease is going to give further tough time to experts and scientists
in the field of medical sciences. It is a fact that when a single infusion is
used as a treatment method, then the patients have obtained profound
advantages. The safety data of these studies have also been encouraging, and it
has been observed as adverse effects to patients have been very small in
numbers. The ongoing and most significant challenge in gene therapy for
Haemophilia patients is the fact that associated comorbidities can make a
viable impact, as well as, giving accessibility to a wider group of people
dealing with Haemophilia. The other issue with the gene therapy is that it is
non-reversible so once it is done with a patient, it cannot be reversed, and
whatever the outcomes are, the burden of those outcomes has to be taken. So,
safety in this gene therapy will always remain a paramount challenge, and scientists
will have to work on this. If safety will always come with a question mark,
then it will be a hard decision for physicians, as well as, patients to decide
whether they should go with the gene therapy or not
It can be concluded in the end that
the process of clinical trials for gene therapy has been a long one, and it has
tested the patience of experts and patients for so many decades with not so much
great results. However, the encouraging thing is that some recent clinical
trials have shown better progress and result in so many ways, but there are
various issues to deal with in the future. The gene therapy for Haemophilia
patients is inaccessible in larger numbers because it is complex, as well as,
expensive. So, the experts have to make it safe and great to use, along with
providing access to a wide range of people across the globe.
Batty, and Pasi, , (2019) 'Gene therapy trials for
haemophilia: a step closer to a cure?', Expert Review of Precision
Medicine and Drug Development, vol. 4, no. 5.
Garcia, , (2000)
'Science and Technology and their Role in Human Health in Developing
Countries', Memórias do Instituto Oswaldo Cruz, vol. 95, no. 1.
Gollomp, K., , Doshi,
B., and Arruda, R. (2019) 'Gene therapy for hemophilia: Progress to date and
challenges moving forward', Transfusion and Apheresis Science, no. 58,
pp. 602-612.
Hanna, , Rémuzat, ,
Auquier, and Toumi, (2017) 'Gene therapies development: slow progress and
promising prospect', J Mark Access Health Policy, vol. 5, no. 1.
Murphy, S., and High,
, (2008) 'Gene therapy for haemophilia', British Journal of Haematology,
vol. 140, no. 5, pp. 479–487.
Nathwani , A. (2019)
'Gene therapy for hemophilia.', Hematology Am Soc Hematol Educ Program,
vol. 1, pp. 1-8.
Rodriguez, (2019) Expert
Q&A: The Current State of Gene Therapy for Hemophilia, [Online],
Available: https://www.hematologyadvisor.com/home/topics/bleeding-disorders/overview-of-and-challenges-in-gene-therapy-for-hemophilia/ [26 March 2020].
WebMD (2020) Understanding Hemophilia -- the Basics, [Online], Available: https://www.webmd.com/a-to-z-guides/understanding-hemophilia-basics#1 [25 March 2020].
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