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A systematic review of gene therapy for haemophilia.Haemophilia A and B are severe X-linked inherited bleeding disorders cause by deficiency of blood coagulation factors VIII and IX respectively....

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A systematic review of gene therapy for haemophilia.Haemophilia A and B are severe X-linked inherited bleeding disorders cause by deficiency of blood coagulation factors VIII and IX respectively. Currently haemophilia is treated with protein replacement therapy using either plasma derived or recombinant coagulation factors, Although replacement therapy is effective a number of challenges still remain. Recent advances in gene therapy potentially offer significant advances in the treatment of haemophilia. Review the disease, treatment options and whether gene therapy is the future for haemophilia treatment.
Answered Same DayMar 13, 2020

Solution

Soumi answered on Mar 31 2020
75 Votes
A SYSTEMATIC REVIEW OF GENE THERAPY FOR HAEMOPHILIA
(UNDERGRADUATE BIOCHEMISTRY DEGREE FINAL YEAR DISSERTATION)
Abstract
Haemophilia has been a dreaded medical condition that has vexed doctors and other medical professionals in the context of using the most useful method for treating it. The disorder is so complex in terms of its pathophysiology and impacts that the management of it amongst the patients has been one of the biggest challenge in medical science. Haemophilia, being a genetic disorder, spreads through inheritance, specifically the X chromosome, thus, making males more vulnerable to acquiring this disease, while women mostly being ca
iers. The cu
ent research has been conducted with the intention to identify the effectiveness of gene therapy, as the most suitable treatment for treating this disease. The conduction of a research encompasses a number of steps, which initiate from the search done for finding out the relevant information, to the follow-up of the investigation with the help of a methodology to finally analysing the findings and infe
ing from them. The secondary sources, which are five selected peer-reviewed journal articles, have been critically reviewed with the support or criticism from other scholarly sources, so that the concepts could be reviewed for the in-depth analysis.
The present research has followed a secondary research methodology, for the purpose of conducting a systematic review of the relevant sources. Positivism philosophy, deductive approach and descriptive design have helped in the achievement of this purpose. The data sources were majorly five peer-reviewed scholarly journal articles, which have been criticised based on other relevant sources. Inclusion, exclusion criteria and a suitable search strategy were used to generate the papers to be reviewed. A critical analysis of the areas reviewed under the topic has been conducted following all ethical considerations over 26 weeks’ time.
Haemophilia a disease caused by deficiency in clotting factor (factor VIII and factor IX). It has X linked inheritance pattern. Based on the deficiency in of two either clotting factor, haemophilia is classified into haemophilia A and B. Deficiency in factor VIII or haemophilia A is more prevalent than Factor IX or haemophilia B deficiency. Consequently, protein replacement therapy used as conventional method of treatment that caused inconvenience and repeated infusion throughout life. However, with advent of gene therapy patients conditions improved with haemophilia. Transient expression of AAV vector in the cells showed success rate of gene therapy, all of which have been conveyed in this chapter of the dissertation. Further, gene therapy clinical trials have shown curative and therapeutic expression in patients. Based on them, the conclusions and recommendations have been drawn.
Acknowledgement
I want to thank _______________________, my Supervisor, and ______________________, my Professor, who helped me to complete this dissertation for my undergraduate final year. I would also thank my peer-group for their support and enthusiasm. Lastly, I would thank my parents and the Almighty for my dedication and will power that I got from their blessings.
Thanking you all,
___________________.
Table of Contents
Chapter 1: Introduction    7
1.1 Introduction    7
1.2 Background of the Research    7
1.3 Rationale of the Research    7
1.4 Research Aim    8
1.5 Research Objectives    8
1.6 Research Questions    8
1.6.1 PICO Question for the Dissertation    8
1.6.2 Sub-questions derived from Key Question    9
1.7 Significance of the Research    9
1.8 Structure of the Dissertation    9
1.9 Summary    10
Chapter 2: Literature Review    11
2.1 Preface    11
2.2 Haemophilia— A Blood Disorder    11
2.3 Types of Haemophilia    11
2.4 Aetiology of Haemophilia    12
2.5 Inheritance of Haemophilia— using example of European Royal Family    12
2.6 Pathophysiology of Haemophilia    12
2.7 Gene Therapy— An Effective method of treating Haemophilia    13
2.8 Advantages and Disadvantages of Gene Therapy    13
2.9 Linking Literature with Cu
ent Research    13
2.10 Gaps in Literature    14
2.11 Summary    14
Chapter 3: Research Methodology    15
3.1 Research Outline    15
3.2 Research Philosophy    15
3.3 Research Approach    15
3.4 Research Design    15
3.5 Type of Research and Data Sources    16
3.6 Inclusion and Exclusion Criteria    16
3.7 Data Collection Method and Search Strategy    16
3.8 Data Analysis Plan    16
3.9 Accessibility Issues and Ethical Considerations    17
3.10 Timeframe    17
3.11 Summary    17
Chapter 4: Data Findings and Analysis (Systematic Review)    18
4.1 Overview    18
4.2 Systematic Review of gene therapy for haemophilia    18
4.2.1 Traditional methods of treating haemophilia    18
4.2.2 Limitations of using Replacement Therapy    19
4.2.3 Rationale of Gene Therapy for Haemophilia    20
4.2.4 Success Rate of Gene Therapy for Haemophilia    22
4.2.5 Challenges of using Gene Therapy for Haemophilia and Feasibility of Addressing them    24
4.3 Summary    25
Chapter 5: Conclusion and Recommendations    26
5.1 Conclusion    26
5.2 Linking Objectives to the Findings    26
5.3 Recommendations    27
5.4 Limitations of the Research    27
5.5 Future Scope of the Research    28
References    29
Appendix    31
Timeframe    31
List of Figures and Tables
Figure 1.1: Structure of Dissertation    10
Figure 4.1: Gene therapy of Haemophilia A    21
Figure 4.2: Gene therapy of Haemophilia B    22
Table 3.1: Gantt chart    31
Chapter 1: Introduction
1.1 Introduction
Haemophilia has been a dreaded medical condition that has vexed doctors and other medical professionals in the context of using the most useful method for treating it. The disorder is so complex in terms of its pathophysiology and impacts that the management of it amongst the patients has been one of the biggest challenge in medical science. Haemophilia, being a genetic disorder, spreads through inheritance, specifically the X chromosome, thus, making males more vulnerable to acquiring this disease, while women mostly being ca
iers (Dahlback, 2018). The cu
ent research has been conducted with the intention to identify the effectiveness of gene therapy, as the most suitable treatment for treating this disease.
1.2 Background of the Research
Haemophilia is a blood disorder that is inheritable due to being passed on from the affected parent to the child through the X chromosome. Studies by a number of authors have focusses on the graveness of this disorder that prevents a person from having clotting of blood. A paper by Kemball‐Cook et al. (2007) has shown that haemophilia is an X-linked chromosomal disorder, which was first developed due to a spontaneous mutation of the gene. Further, consequent inheritance took the disorder beyond its epicentre, thus, leading to the spread of the disorder through the world, presently. The history of Haemophilia dates back to 1837, when Queen Victoria developed this disease first due to the spontaneous mutation of her gene, thus causing a spread of this disease to the other parts of the world (Mannucci and Tuddenham, 2001).
There are a number of therapies that have been used; previously and even now, as stated by Nathwani et al. (2014), such as replacement therapy and chemical treatment. However, the challenges imposed by these therapies have been made the recent researches infer that these methods are not the best ones for treating haemophilia. Therefore, this cu
ent research topic was developed on the basis that gene therapy, which is a recent development in the field of medical science, could be implemented potentially to treat this disease. Hence, the systematic review has been done not only to support this potentiality, but also to critically analyse the benefits and limitations of the same.
1.3 Rationale of the Research
The key issue of this research has been identified to be the use of the traditional methods of treatment for haemophilia A and B. as stated by Nathwani et al. (2014), the protein replacement therapy has been used since a long time to treat haemophilia and even now, it is in common use. However, it is an issue because there are a large number of demerits to this therapy such as the incapability of establishing vascular growth with the patient, unsuitability of many individuals to be treated with this therapy and many organs not responding to it (Dahlback, 2018). Therefore, presently, it is a major concern because in the new developments of biotechnology, biochemistry and genetics, the usage of gene therapy has emerged. According to Giangrande (2016), gene therapy has been assessed to have a high rate of success and is effective across both the types haemophilia that are A and B. Therefore, keeping in mind, the need to enhance the use of this method increasingly and avoiding its demerits, this research sheds light upon the appropriateness as well as the effectiveness of using it for treating haemophilia. Thus, the study conducted has been a systematic review of the relevant peer-reviewed secondary sources.
1.4 Research Aim
The aim of this research is to conduct a systematic review for the efficacy of gene therapy for treating haemophilia. The concerned types for treating with gene therapy has been both haemophilia A and B, which is why the research has dealt in analysing its implication in case of both these types of haemophilia. Besides, the research also aims to review why the usage of replacement therapy is not an effective one, on account of the challenges it imposes during the process, therefore, finally recommending the appropriate use of gene therapy.
1.5 Research Objectives
The research aim has led to the persuasion of the following objectives:
· To understand the condition and impact of haemophilia
· To identify the pathophysiology of the disorder, along with the ways of treating it
· To analyse the significance of using gene therapy for treating haemophilia A and B instead of replacement therapy
· To suggest the suitable ways of applying gene therapy by considering its success rates and challenges
1.6 Research Questions
1.6.1 PICO Question for the Dissertation
Based on the research objectives and aim, the following PICO question could be derived:
P (Problem/Patient): Haemophilia A and B
I (Intervention): Gene therapy
C (Comparison): Protein replacement therapy using either plasma derived or recombinant coagulation factors
O (Outcome): Treating and curing Haemophilia
PICO question: What is the effectiveness of using gene therapy for treating and curing Haemophilia A and B, in comparison to protein replacement therapy using either plasma derived or recombinant coagulation factors?
1.6.2 Sub-questions derived from Key Question
· What is Haemophilia A and B?
· What are its pathophysiology, impacts and treatment methods?
· How is gene therapy better than replacement therapy?
· How can gene therapy be used for treating Haemophilia?
1.7 Significance of the Research
The key significance of this research is that since it is a systematic review, therefore, it has made use of a varied range of secondary literature that pertains to the research topic. Therefore, the reader gets a clear idea about the issue of haemophilia, its impact, the best treatment options for it and the use of gene therapy. Thus, this paper can serve as a source of information for not only academic purpose, but also for further research purposes that would encompass the application of gene therapy in this field. Moreover, the in-depth knowledge gained from the systematic review of the traditional therapies would give the scope for analysing the benefits of using gene therapy over the others.
1.8 Structure of the Dissertation
The dissertation has been sub-divided into five chapter, namely as below:
Figure 1.1: Structure of Dissertation
(Source: Researcher)
1.9 Summary
From this chapter of the dissertation, a basic idea about the research topic could be derived. It was identified that Haemophilia is a genetic blood disorder that is inherited through the X-linked chromosome, which is why mostly males have it. The research rationale gave a clear idea on the need to conduct this systematic review for understanding the importance of gene therapy for treating this disorder. These led to the identification of the aim, objectives, PICO question and sub-questions. Finally, the significance of the study and the structure of the dissertation have provided a map for proceeding with the forthcoming chapters.
Chapter 2: Literature Review
2.1 Preface
The conduction of a research encompasses a number of steps, which initiate from the search done for finding out the relevant information, to the follow-up of the investigation with the help of a methodology to finally analysing the findings and infe
ing from them. This research has also been no exception in this regard, where an in-depth knowledge about the background of this study was conducted using the prevailing literature. The secondary sources, which are five selected peer-reviewed journal articles, have been critically reviewed with the support or criticism from other scholarly sources, so that the concepts could be reviewed for the in-depth analysis.
2.2 Haemophilia— A Blood Disorde
Haemophilia has been a major concern for all throughout the world due to the issue of excessive, uncontrolled bleeding caused to a person suffering from this disorder. As mentioned by High (2012), a person suffering from haemophilia tends to bleed profusely and the bleeding does not stop readily because the blood coagulation factors VIII and IX are lacking within the person. The gene responsible for this disorder is linked to the X chromosome of the individual, which is why females can be a ca
ier of this disorder, with one of X chromosomes, being affected, while the other being normal (Kemball‐Cook et al. 2007). However, as argued by Nathwani et al. (2014), since males have one X and one Y chromosome, therefore, if their mother is affected, they too inherit the disorder through the inheritance of the affected X chromosome from their mother. Nevertheless, according to Giangrande (2016), a haemophilic father and a ca
ier mother can have a 50% chance of having a haemophilic daughter, although the chance is very rare.
2.3 Types of Haemophilia
There are generally, two key types of haemophilia suffered by human beings. As mentioned by Giangrande (2016), these are haemophilia A and haemophilia B. Although haemophilia at large causes an uncontrollable profusion of blood; however, the cause for this profuse bleeding is the lack of the coagulation factor VIII being in haemophilia A, while that in case of haemophilia B is the absence of the coagulation factor IX in case of haemophilia B. Other than this criterion, there are no other major differences between the two mentioned types of haemophilia. However, there have been found that there are a more number of occu
ences of the haemophilia B amongst the males than the occu
ences of the haemophilia A in them. Although women have a rarer tendency of developing this disease, yet the issue is same in case of them as well.
2.4 Aetiology of Haemophilia
The key cause of haemophilia is the inheritance of the mutated gene, which is contained within the X-linked chromosome. Therefore, it more commonly affects the male individuals than it does to the female individuals. As supported by Nathwani et al. (2017), mutation in the genetic make takes place spontaneously within an individual, which is why the occu
ences of haemophilic gene is first initiated amongst the individual. Further, with the incidence of sexual contact, the gene is transfe
ed to the zygote during pregnancy, thus causing the baby to develop this disease. If the baby is a boy, they would certainly have it, while if the baby is a girl, as argued by Nienhuis et al. (2017), she might not have it due to she being a ca
ier of the same on account of her double X chromosomes.
2.5 Inheritance of Haemophilia— using example of European Royal Family
The prevalence of haemophilia as a genetic disorder was not aware to many people until the year 1837. As stated by Mannucci and Tuddenham (2001), the first spread of haemophilia as a genetically inherited disease was established when it was found that it came initially from Queen Victoria, who was the then Queen of England. She had developed this disease due to a spontaneous mutation of her genetic make-up thus, leading to an unusual disease for the population at that time, who were not quite aware of the syndrome. During the wars, the disease spread to the other countries as well such as Russia, Sweden and Greece, which is why the issue worsened. Not only that, as argued by Rogers and Herzog (2015), the inheritance of this disease being X linked, most of the men were getting affected, while the women used to be only ca
iers. As a result, this disease became popularised as the Royal Disease out of the Royal Gene (Mannucci and Tuddenham, 2001).
2.6 Pathophysiology of Haemophilia
The pathophysiology of Haemophilia is a very direct and simple pathway followed for the occu
ence for the disease. As mentioned by High (2012), the key reasons behind the causation of the haemophilia is the lack of the coagulation factors VIII and the coagulation factors IX within the blood of certain human beings, which is why the individuals suffer from an unstoppable bleeding syndrome. As stated by Dahlback (2018), the factor VIII is highly inefficient deletion of B domain, results in 17-fold increase in mRNA expression. Therefore, its efficiency in clotting the blood is indispensable. Not only that, the site of binding of the factor IX is weakened, which is why it also becomes incapable of stopping...
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