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Sickle cell anemia is severe, chronic and even fatal disease. It causes red blood cells to break down and and sickle (form a crescent shape). It occurs due to a point mutation in the Red blood cells which blocks blood flow therefore there is a chronic deprivation of oxygen which leads to complications such as damage to nerves, kidneys, liver, spleen and other organs in the body. Therefore it is important to find a cure, Gene therapy is one of the experimental techniques being researched to treat sickle cell anemia. It involves various genetic technologies that either cure sickle cell disease or make it milder which reduces symptoms and prevents complications. For example, technologies such as zinc finger nuclease are used to snip out the defective gene (HBS) and add in the correct one and lentiglobin gene therapy which introduces a functioning version of the HBB gene into the patients hematopoietic stem cells via a viral vector. These technologies treat sickle cell anemia as they remove the defective genes and replace them with correct functioning ones allowing them to live without complications which improves their quality of life.
About the genetic disease
Name- Sickle Cell Anemia
Cause- It is caused by a mutation in the gene in which forms abnormal haemoglobin (haemoglobin S) that causes red blood cells to become rigid, sticky and misshapen. This sickle cell gene is inherited and passed on through each generation through autosomal recessive inheritance patterns (rr). This means for the child to inherit the disease both parents must be a carrier and pass on the sickle cell gene. However if only one parent passes on the sickle cell gene this child will be a carrier meaning he/she will contain both normal and sickle cell haemoglobin.
Symptoms
- Fatigue and anemia- This occurs due to low oxygen levels in the body
- Swelling and inflammation of the hand or feet
- Arthritis
- Pain crises in the joints and can be sudden in the chest.
- Hematuria or blood in urine.
- Delayed development
- Pallor or yellow skin and eyes
- Shortness of breath.
- Acute Chest syndrome
- Recurring bacterial infections.
- Sudden pooling of blood in the spleen and liver congestion.
- Lung and heart injury.
- Leg ulcers.
- Death of portions of bone
- Eye damage
Age of onset
Sickle cell anemia is usually diagnosed at birth. However, the age of onset can range from 2 months to 176 months. The symptoms of the disease are often prevalent from 4 months of age.
Incidence
Around 70,000 to 100,000 Americans have sickle cell anemia as it is one of the most common inherited blood disorders in the USA. It is most common in ethnic groups such as African americans and hispanics.
Estimates of SCA:
- SCD occurs among about 1 out of every 365 Black or African-American births.
- SCD occurs among about 1 out of every 16,300 Hispanic-American births.
- About 1 in 13 Black or African-American babies is born with sickle cell trait (SCT).
- Survival to adulthood for children with SCD is predicted to be 99 percent in London, 97 percent in Paris, and 94 percent in the U.S.
Prevalence
Sickle cell anemia is most prevalent in areas where outbreaks of malaria occur or have occurred in the past. This is mostly in Africa or in those who have ancestors from Sub saharan Africa, indian, Saudi Arabia and Mediterranean countries.This distribution has occurred due to the spread of malaria in the past which was very common in these countries. As a result the sickle cell trait obtains a survival advantage against malaria and that the selection pressures caused by malaria has resulted in more occurrences of the sickle cell allele. Due to human migration over the years individuals obtaining the sickle cell allele carried it with them all over the world.
The global birth prevalence of the disease is 0.11% but it fluctuates from country to country 5% of the world’s population are carriers of the disease However it is most prevalent in Africa. There are more than over 200,000 cases of SCD in Africa
The prevalence of the sickle cell trait (Carriers of the disease) is from between 10%-40% across equatorial Africa and decreases to between 1% and 2% on the north African coast and In west African countries such as Ghana and Nigeria, the frequency of the trait is 15% to 30% whereas in Uganda there are tribal variations,as it is 45% among the Baamba tribe.
Range of genes/mutations involved
The haemoglobin beta gene located on chromosome 11 is responsible for sickle cell anemia as it causes a mutation. Haemoglobin A is the normal, healthy haemoglobin gene . The red blood cells that contain this form of haemoglobin are round, smooth and can pass through blood vessels. However individuals that have sickle cell anemia obtain the haemoglobin S which consists of abnormal haemoglobin molecules that stick to each other and form a curved red blood cells which causes them to become stiff and rigid forming a sickle shape. The red blood cells then pile up which causes blockages and damages vital organs and tissues.
Sickle cell anemia is caused by a single point mutation, where a single nucleotide base is changed, added or removed from a sequence of DNA or RNA in the corresponding position on the complementary strand. The point mutation occurs in the b-Globin chain (beta globin) of haemoglobin which leads to the hydrophilic glutamic acid being replaced with the hydrophobic amino acid valine at the sixth position.This occurs as the HBB gene( the gene that codes for beta globin) is replaced with its variant HBS which produces sickle cell disease. The resulting protein still obtains 147 amino acids however due to the single nucleotide change the normal haemoglobin gene is transformed into a sickle cell one.Therefore the sequence for the Mutant haemoglobin contains the code GTG instead of GAG.
What is known about the protein product of the gene(s) involved?
The protein product of the HBB gene is a protein called Beta Globin. This is a small part of the larger protein Haemoglobin which is made up of the beta globin and alpha globin (HBA) subunits. These are responsible for carrying oxygen around the body . Mutations in the HBB produce different variations of the proteins which correspond with diseases such as sickle cell anemia.
For a normal haemoglobin molecule. One HBB gene and one HBA1 gene combine to form a dimer and then 2 dimers combine to form the 4 chain tetramer which is the haemoglobin A molecule. However, for sickle cell anemia HBS, A HBB variant is produced by a point mutation in which the codon GAG is replaced by GTG. HBS replaces both beta globin subunits in haemoglobin, or it can replace one and the other beta globin would be replaced with sickle-hemoglobin C (HbSC) or S-beta thalassemia (HbSBetaThal) which are all variations of sickle cell disease.
This occurs due to the hydrophobic valine which has replaced the hydrophilic glutamic acid. The hydrophobic valine will be located on the outside of the haemoglobin protein facing the water even though it is hydrophobic. Due to the hydrophobicity of the valine when 2 or more valines interact they will stick to one another shielding themselves from the cytoplasm. As the hydrophobic valines from different haemoglobin proteins adhere to one another, long chains begin to form within the red blood cells . This is what causes the sickling of the red blood cells.
How genotype contributes to disease phenotype (i.e. how do changes to the protein result in the symptoms)? There are different genotypes for sickle cell anemia individuals with the genotype AS obtain the sickle cell trait phenotype whereas individuals with the SS genotype obtain the sickle cell disease phenotype. The genotype of the individual is what contributes to disease phenotype. The changes in the protein (haemoglobin A) result in the red blood cells to form a sickle cell shape. Due to the abnormal shape of the blood cells they get stuck in blood vessels which cause complications as they slow/block blood flow to parts of the body. These sickle shaped cells also can die prematurely , leading to anemia. As blood flow is blocked and inadequate oxygen is circulated around the body it causes pain, high BP in lungs, stroke, pulmonary hypertension, organ damage, blindness, gallstones and many other complications.
Inheritance patterns
Sickle cell anemia has autosomal recessive inheritance patterns. This means that both parents are a carrier of the sickle cell trait. However they usually do not show symptoms of the disease. The offspring will inherit 2 mutated genes, one from each parent. When two parents who are carriers of the sickle cell disease produce offspring, the chance that the offspring will inherit the disease is evident in fig 1 and fig 2. This is the most common inheritance patterns which are highly prevalent in Africa.
In the following punnett squares both parents are carriers of the sickle cell allele and it is evident that the offspring produced would have a 25% chance of inheriting sickle cell disease, a 50% chance they will be a carrier of the disease like their parents and and a 25% chance that they will not inherit the disease.
Current methods of diagnosis and treatment
There are many methods of diagnosis and treatment for sickle cell anemia for example :
A blood test can test for Haemoglobin S in which a blood sample is taken from a vein in the arm, in younger children it is taken from the finger or heel. This is then transferred to a laboratory where it will be screened for Haemoglobin S. If the test results are negative, this indicates that there is no sickle cell gene present, however if it is positive then more tests will be conducted to identify if one or two sickle cell genes are present. If the test is positive it is not always the case that the individual has sickle cell disease they may only have sickle cell trait therefore additional testing needs to be conducted to gain a definite diagnosis.
Further testing is also necessary for those diagnosed with sickle cell anemia this includes more blood tests and urine tests to monitor the patient for kidney problems or infections. Doctors may also suggest a transcranial doppler ultrasound screening (TCD). This is a procedure which applies sound waves to observe blood flow in the brain. It is used to detect the probability of a stroke and ensure the patient is receiving treatment when required.
In babies sickle cell disease is usually diagnosed by sampling some of the fluid around the baby inside the mother’s womb(amniotic fluid) to detect sickle cell gene Gel electrophoresis can be conducted to determine whether the child has inherited sickle cell disease or trait from both parents this is done through DNA profiling.
Treatment
A common method of treatment is bone marrow transplant. This transplant is usually for patients under the age of 16. First the patient is treated with chemotherapy to get rid of the unhealthy bone marrow. Then via a donor (their siblings) the patient will receive healthy bone marrow which is transferred to them through a vein. This is the only known cure for sickle cell disease.
Doctors also recommend common medicines to treat sickle cell anemia such as antibiotics such as penicillin which prevents infections, pain relieving medicines and Hydroxyurea which reduces the frequency of painful crises and decreases the need for blood transfusions. It works by stimulating the production of fetal haemoglobin- a form of haemoglobin prevalent in newborns that prevents the formation of sickle cells
Hydroxyurea seems to work by stimulating production of fetal hemoglobin — a type of hemoglobin found in newborns that helps prevent the formation of sickle cells making sickle cell disease milder.
Gene therapy
Gene therapy is an experimental technique in which healthy, normal genes (structures of DNA) are introduced to a patient to treat their genetic disease. The healthy genes replace defective or missing genes within the cell. Gene therapy is used to treat sickle cell anemia by altering the patient’s hemoglobin genes or introducing a healthy copy of the mutated gene to the body.
One of the strategies applied for gene therapy is bone marrow transplant, bone marrow transplant applies a combination of gene therapy and chemotherapy to treat sickle cell anemia. This process involves altering the patient’s hematopoietic stem cells. Before undergoing the transplant patients, undergo chemotherapy to eliminate their existing bone marrow. For the process to proceed the patient must have a donor with matched DNA this is usually siblings or someone with the same bone marrow type. The patient’s own bone marrow is taken then the defective stem cells are isolated. In the laboratory the normal healthy gene is inserted into these stem cells to prevent them from sickling then the bone marrow cells are then transferred back to the patient.
Other techniques are also being experimented on such as zinc finger nuclease and lentiglobin.
Zinc finger nuclease
zinc finger nucleases (ZFNs), are proteins specifically designed to grab onto a sequence of DNA and cut it, snip out one version of a gene and then another technique is used to replace it with the correct one. These work by binding to the DNA at a specific targeted sequence and creating a double strand break. These can effectively mutate or eliminate genes of interest . For example, ZFN can target disruption of the BC11A gene, this gene is responsible for turning off the production of fetal haemoglobin. If the BC11A gene is turned off the production of fetal haemoglobin resumes. This prevents the sickling of the blood cells therefore making sickle cell disease milder.
Lentiglobin
Lentiglobin is a viral vector construct which contains the normal gene for haemoglobin.The healthy version of the B_globin gene is inserted into the patients blood stem cells. This produces normal red blood cells instead of sickle cell ones.
A functioning copy of the haemoglobin gene, this is packaged into a lentiviral vector, this contains the HIV virus (human immunodeficiency virus) which is highly effective at inserting genes into cells (the vector has been modified so it cannot pass on hiv infection).
First the patient’s own healthy stem cells are collected from their bone marrow.
The lentiviral vector will then be inserted into the patients stem cells (outside the body) this contains the functioning copy of the haemoglobin gene . The corrected gene will be inserted back into the Dna of the patient. Which will produce a modified stem blood cell which will grow and produce new blood cells containing normal haemoglobin. During this process chemotherapy is applied to remove defective stem cells.
Risk/Benefit Analysis of inquiry question
Benefit
As research on gene therapy techniques increases, gene therapy can be applied in the future to act as a cure for sickle cell anemia this will increase survival rates and prevent complications.
If gene therapy is applied:
The Quality of life will improve for those suffering with sickle cell anemia, this is a benefit as it can prevent complications that arise from sickle cell anemia and can completely eliminate the disease.
The effects will be long lasting and will ensure future generations do not inherit the disease. When the defective genes are removed these will not transfer to the offspring of the following generation.
It will not require a correct match of DNA as there are technologies such as ZFN that exist whereas for processes such as bone Marrow transplant a correct match of DNA is required for the patient to be cured.
A new field of medicine can be created this is a benefit as gene therapy can be used to not only treat sickle cell anemia but many other diseases that occur due to defects in genes such as cystic fibrosis, cancer, heart disease etc..
Risks
Immune response-As a result of a viral vector being introduced to the body, the immune system fights off bacteria and viruses and may do so for the viral vector. This results in inflammation and can cause serious illnesses and even death. This has occurred in many cases for example, in 1999 Jesse Gelsinger had a rare liver disorder, he undertook gene therapy to overcome it however he died due to complications of an unwanted inflammatory response due to the viral vector being introduced to his body .
Targeting the wrong cells.- In order for gene therapy to work successfully the introduced gene must integrate itself into the patients DNA. However it can sometimes integrate itself at a different location infecting another gene. This causes healthy cells to be damaged and can lead to other diseases such as cancer and leukemia.
There is always the risk that when the virus is used to deliver the gene into the patient’s body that it can integrate into the patient’s reproductive cells. This can cause significant changes that can be passed on to the patient’s offspring.
Comparison with prior methods of treatment
The prior and current methods of treatment for sickle cell anemia include antibiotics, pain relieving medications, hydroxyurea and bone marrow transplant these are the most common methods of treatment that have been used to this day. However as technology advances, there have been many experimental techniques such as gene therapy and genetic editing.
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