Abstract
The following paper is about genetic disorders, the one in which has been discussed in great detail being hemophilia, the gene therapies for such genetic diseases and the advancement that have been made in this particular field of study. As you read you find the definition of gene therapy and what it involves as well as how genetic diseases happen and how they are treated. The genetic disease of hemophilia is also discussed in great detail. Hemophilia is an x-linked genetic disease where your blood can't clot and the sufferer experience episodes of excessive which is just one of the many symptoms. It can be divided into two groups hemophilia A and hemophilia B. The gene therapy adeno-associated viral (AAV) vectors is currently being studied as a way to treat those who suffer from hemophilia.
Introduction
From this crash course on gene therapy I have developed a better understanding of genetic diseases and have explores how gene therapies are being developed in order to deal with these diseases. In this final assignment I will be discussing what gene therapy and genetic diseases are and will be focusing on one genetic disease, Hemophilia, in detail. Concerning this disease, I will talk about the genetic bases of this disease such as the genes involved, inheritance and what type of disease it is. I will also discuss the history of the gene therapies for this condition and any therapies currently under development.
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Genetic disorders are caused by mutations in the DNA of the cells. These mutations can be small and not cause any harm to an individual, such as having an extra finger, but then some mutations can cause complications and difficulty to an individual. These genetic disorders can be treated by gene therapy. Gene therapy is an experimental technique that uses genes to treat or prevent disease. Gene therapy enables doctors to introduce normal genes into cells in place of missing or defective ones in order to correct genetic disorders. Gene delivery is crucial as these genes cannot just be placed into the cell so a vector, a genetically developed carrier, is used to transport this gene into the cell. Viruses can also be used to treat these diseases. Two type of viruses are used. They are Ex-Vino, this is when the cells are taken out modified and then put back in, and In-Vino, this is when the virus is injected into the gene directly inside the body. Gene therapy uses a drug to coax the patient’s own stem cells into their blood where they are filtered out. These are cultured and then infected with a retrovirus or lentivirus. The lentivirus vector integrates into the genome (all the genetic material information in an organisms) and expresses a missing gene with those cells. The patients altered stem cells are then injected back into them.
Genetic Basis of Hemophilia
A gene disorder that I found in great interest is Hemophilia. Hemophilia is an inherited bleeding disorder where the blood doesn’t clot properly. It is caused when blood does not have enough clotting factor A clotting factor is a substance, a protein, found in the plasma of the blood. Clotting is also known as coagulation which is the process by which blood changes from a liquid to a gel, forming a blood clot. Those who suffer from Hemophilia are unable to carry out this process. Hemophilia is a rare genetic disorder. Hemophilia affects males only but there are rare circumstances when a female can be affected with the disorder. I will discuss this in detail later. Hemophilia can be divided into two different groups. Hemophilia A and Hemophilia B. [6: https://www.mydr.com.au/heart-stroke/haemophilia-what-is-it [March 4, 2019]]
Hemophilia A is caused by genetic mutations in the F8 gene. This gene is responsible for making the Factor VIII (FVIII) protein. This means your body doesn’t have enough of a protein called factor VIII which is needed to make clos and stop bleeding. The severity of Hemophilia A depends on the amount of how little factor VIII an individual has. Hemophilia A affects 1 in 5,000 to 10,000 males. AROUND 60% TO 70% of people affected by Hemophilia A have the severe form of the genetic disease. The diagnosis of hemophilia A is made through clinical symptoms and specific laboratory tests to measure the number of clotting factors in the blood. The signs and symptoms of hemophilia vary depending on the level of clotting factors. In a severe case, the sufferer may experience spontaneous bleeding. A mild hemophilia A sufferer may only notice bleeding after a serious injury or after surgery or other procedures, such as having a tooth removed. Women with a mild case often have heavy periods and can bleed heavily after childbirth. A moderate hemophilia A sufferer will most likely not notice any bleeding problems until after an injury or sometimes they may bleed without injury. A sufferer of severe hemophilia A may have frequent episodes of bleeding, often into the joints and muscles without being able to find out the cause of such occurrence. They may also experience blood in the urine (Hematuria). Bleeding can also occur in the brain (Intracranial hemorrhage), symptoms of this may be prolonged headaches, throwing up, sleepiness, sudden weakness, problem walking or double vision. Infants with the severe form may bleed abnormally from their mouth and develop ‘goose eggs’ on their heads (collections of blood under the scalp). [7: https://www.webmd.com/a-to-z-guides/hemophilia-a#1-1 [March 4, 2019]] [8: https://my.clevelandclinic.org/health/diseases/14083-hemophilia [March 5, 2019]] [9: https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-B [March 6, 2019]]
Hemophilia B is a bleeding disorder that slows the blood clotting process. This genetic disorder is caused by a mutation in the F9 gene which causes a missing or defective factor IX (FIX), a clotting protein. Hemophilia B is four times less common than hemophilia A. It affects 1 in 25,000 to 30,000 males. People with hemophilia B bleed longer than other people. This can happen internally or externally. How frequently and how serious a person bleeds depends on how much FIX is in the plasma. A regular level of FIX is about 50% and above. A person who has hemophilia B has below this level of FIX. The symptoms of this genetic disorder are determined by the severity of the disease. Mild hemophilia A sufferer has about 6% to 49% FIX in their blood. The sufferer experiences the same symptoms as a sufferer of mild hemophilia A, bleeding after serious injury or surgery, etc. A suffer of moderate hemophilia has about 1% to 5% of FIX in their blood. They experience bleeding episodes after surgery. A person who has a severe case of hemophilia B has less than 1% of FIX, an extremely low amount, in their blood. They suffer from bleeding after surgery and have frequent spontaneous bleeding episodes. [10: https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-B [March 6, 2019]] [11: https://my.clevelandclinic.org/health/diseases/14083-hemophilia [March 6, 2019]] [12: https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-B [March 6, 2019]]
Both hemophilia A and hemophilia B are inherited in an X-linked recessive pattern. The genes that are involved in this genetic disorder are located on the X chromosome. Males have one X chromosome. One mutated copy of this gene in each cell is enough to have the condition occur. Females have two X chromosome. For the disorder to occur a mutation would have to occur in both copies. Hemophilia, like I have mentioned previously, is less likely to occur in females because it's unlikely that they would have to mutated copies. In X-linked inheritance fathers cannot pass X-linked diseases to their sons as sons receive their fathers Y chromosome and their mothers X chromosome. However, fathers will pass on their X chromosome to their daughters, meaning they will be obligated carriers. A female with one altered copy of the gene in each cell is a carrier of the genetic disorder. This means that each of her sons will have a 50% chance of having hemophilia and her daughter has a 50% chance of being a carrier. A family may have children with the hemophilia gene and children without it. It is also possible for all the children in the family to inherit the normal gene or all to inherit the hemophilia gene.(Visual representation of genetic inheritance of hemophilia)
Gene Therapies Currently Under Development
An area of major interest to both physicians and patients is when a gene therapy product for hemophilia might be available. Since the isolation of the genes encoding FVIII (5) and FIX (6), hemophilia has been a target for investigation of gene therapy, and the level of activity in terms of clinical trials of gene therapy for hemophilia reflects this. Decades of preclinical and clinical work have resulted in the current successful phase I/II gene therapy trials for hemophilia. Currently open studies use adeno-associated viral (AAV) vectors. AAV is a replication defective member of the parvovirus family and is nonpathogenic in humans.The recombinant vector has tropism for a range of target tissues including the liver. They are stabilized in an episomal form so that long term expression can occur only with delivery into long lived, post-mitotic cell types. The vector integrates at a very low frequency and is typically lost from replicating cells. The size of the AVV genome ( ̴4.7 kb) limits the size of the packaged transgene. The expression is accomplished slowly by a combination of distinct strategies. The entire process can be seen more clearly and more in depth in the diagram below [14: Arruda VR, Samelson-Jones BJ. Obstacles and future of gene therapy for hemophilia. Expert Opin Orphan Drugs 2015; 3: 997–1010. DOI: 10.1517/21678707.2015.1069179. [March 7, 2019]] [15: Wang, L., Wang, H., Bell, P., McMenamin, D. and Wilson, J.M, (2012) Hepatic gene transfer in neonatal mice by adeno-associated virus serotype 8 vector. Hum. Gene. Ther., 23, 53-539. [March 7, 2019]] [16: Arruda VR, Samelson-Jones BJ. Obstacles and future of gene therapy for hemophilia. Expert Opin Orphan Drugs 2015; 3: 997–1010. DOI: 10.1517/21678707.2015.1069179. [March 7, 2019]] [17: McIntosh J, Lenting PJ, Rosales C, et al. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood 2013; 121: 3335–3344. DOI: 10.1182/blood-2012-10-462200. [March 8, 2019]]
The most difficult problems in hemophilia care at this point in time is patients who develop inhibitors to the infused factor. This happens in around 20% - 30% of hemophilia A patients. But less frequently in those who suffer from hemophilia B. Currently there is an immune tolerance induction regimen (ITI), where patients are infused with large doses of clotting factor daily. This strategy results in eradication of the inhibitor and restoration of normal FVIII pharmacokinetics. This is an excellent setting for a gene therapy strategy as it will expose the patient to continuous levels of FVIII without the need of daily infusions. [19: Wright, J. and Paisley, S. (2003) The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia, 9, 418-435 [March 10, 2019]] [20: Finn, J.D. Ozelo, M.C., Sabatino, D.E., Frank, H. W.G., Merricks, E.P., Crudele, J.M., Zhou S., Kazazian, H.H., Lillicrap, D., Nichols, T.C. et al. (2010) Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood, 116, 5842-5848. [March 11,2019]]
Conclusion
To sum up everything that has been stated gene therapy has become a promising strategy for treating many incurable diseases, whether acquired or heritable. However, the main challenge facing gene therapy, which prevents its widespread use in vivo, is to find efficient delivery systems capable of protecting and delivering the transgene to the targeted cells. Hemophilia is a bleeding disorder that slows the blood clotting process. People with this disorder experience prolonged bleeding following an injury, surgery, or having a tooth pulled. The major types of this disorder are hemophilia A and hemophilia B. Recent clinical trials using AAV-mediated gene transfer have revealed the tremendous potential of gene therapy for the treatment of hemophilia. Overall there has been huge progress in the world of gene therapy and there is continuous discoveries and theories being put out which is bringing us closer to being able to combat all genetic diseases through gene therapy.
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