(The title of my project changes with time as one will observe from one blog to another)
Definition:
- Sickle cell diseases-one of the commonest genetic diseases,comprises a group of disorders characterized by the presence of at least one hemoglobin S allele (an alternative form of a gene).
- It causes the red blood cells to deform and become sickle/crescent shaped.
- Sickle cell diseases are caused by a mutation in the hemoglobin subunit gene(HBB).
- Sickle hemoglobin(HbS) is as a result of a single base-pair point mutation in the beta globin gene resulting in the substitution of the amino acid valine for glutamic acid in the beta globin chain.
- The misshapen red blood cells clump together and get stuck in blood vessels,blocking blood flow and depriving tissues and organs of oxygen-rich blood.
- The commonest type of SCD occurs in individuals homozygous for the HbS allele.
- The most common sickle cell disease is sickle cell anemia
How does one inherit sickle cell disease?
Sickle cell disease is inherited in an autosomal recessive pattern. This means a child will not inherit the disease unless both parents pass down a defective copy of the gene. People who inherit one good copy of the gene and one mutated copy are carriers. They are clinically normal, but can still pass the defective gene to their children.
What is sickle cell trait?
Sickle cell trait does not turn into sickle cell disease. If someone has sickle cell trait and his partner has sickle cell trait they may produce a child with sickle cell disease.
The sickle cell trait is advantageous as the patients have nil chances of contracting malaria.
Those with the sickle cell trait may experience health complications under stressful conditions such as:
- Dehydration
- Low oxygen in the air
- High altitudes
- High pressure in the atmosphere
Symptoms of Sickle Cell Anemia
Acute symptoms
- Sepsis
- Hypersplenism
- Dactylitis
- Acute Chest Syndrome
- Pain Crisis
- Osteomyelitis
- Stroke
- Splenic sequestration
- Priapism
Chronic symptoms
- AVN of the hip joint
- Infertility
- Hyposthenuria
- Cholelthiasis
- Infertility
Demographic mostly affected
Sickle Cell Diseases primarily affect people with African,Hispanic and Mediterranean ancestry.
The main focus of this research is the demographic in Africa specifically sub-Saharan Africa where malaria prevalence is highest.
Why is Sickle Cell Prevalent in some demographics than others?
The evolution of the disease in Malaria prone regions-this mutation was to help people tolerate malaria.
The frequency of Sickle Cell Anemia is highest in equatorial low altitude regions of Africa.
Sickle Cell Anemia has a low prevalence in southern and northern parts of Africa as malaria has a low prevalence in these regions.
Evidence shows that about 90% of the world’s sickle cell disease population lives in Nigeria,DRC and India.
Sub-Saharan Africa
This is the region in Africa below the Sahara Desert and consists of 47 countries.
The countries in Sub-Saharan Africa with the highest prevalence of SCD cases are:
- Cameroon
- Democratic Republic of Congo
- Gabon
- Ghana
- Nigeria-globally has the highest cases of SCD
- Uganda – about 45% prevalence in some parts
Statistics.
The impact of Sickle Cell Diseases(SCD) is global and increasing. In the USA an estimated 100,000 individuals have the disease and in Sub-Saharan Africa about 300,000 children are born with SCD annually and face a 75-90% mortality rate by the age of five due to infectious diseases.
Sub-Saharan Africa comprises all the countries below the Sahara desert in Africa.
Effects of SCD on individuals
The individuals who survive premature death due to the disease are forced to live in constant pain, weak immune systems that make them susceptible to all types of infections, dehydration and shortness of breath. Most children growing up with sickle have a constant fear of not reaching adulthood and when they do, most of them succumb to the severe symptoms and end up helpless and jobless as their symptoms do not permit them to hold a demanding job. They are told that they should not let their condition limit their life. But how can they not; when it is what determines how they live because, any wrong move and they end up in the hospital, the repercussions are a high hospital bill that leaves a huge dent in their finances and those of their guardians.
Treatments for SCD
The available treatments for sickle cell that can be used to manage the symptoms of the disease are:
- hydroxyurea
- L-glutamine
- Voxelator
- Crizanlizumab
These medications aid in alleviating the pain and managing the other symptoms which enable the patients to manage their suffering. The downside of these available treatments is that they are not available to all patients with sickle cell.Most of these patients have low incomes and meeting the high cost of the medications becomes impossible, most are left in crippling debt where they are forced to obtain loans so that they can get the medication they need.
Approved Cures for Sickle Cell Diseases
- Hematopoietic stem cell transplant
- Gene therapy comprises of gene editing and gene addition
Patients who can afford the stem cell transplantation are faced with a challenge of obtaining a donor .Finding a compatible donor is not guaranteed thus most patients are left with crushed dreams of getting cured of the disease that limits them. The procedure involves risk of graft vs host disease where the patient’s body may reject the transplanted cells. The mortality rate after transplantation is about 5% which is high as no one wants to take such a risk on their lives. These shortcomings coupled with the inability of the medications to get rid of the symptoms of sickle cell prompted the revolutionary discovery of CRISPR, a gene editing technique that involves transplantation of genetically edited cells and gets rid of the sickle cell symptoms.
CRISPR is an acronym for clustered regularly interspaced short palindromic repeats(CRISPR) ; a gene editing technique that is used to correct the mutation in the hemoglobin that results in the production of mutated red blood cells. The application of this technique is meticulous and occurs in distinct phases, which are:
- Identifying the mutated cells and extracting hematopoietic stem Cells: In sickle cell disease, a specific mutation in the HBB gene results in the production of abnormal hemoglobin (HbS). Scientists first identify the precise location of this mutation in the patient’s genome then the cells are extracted from the patient’s bone marrow
- Designing CRISPR Components: Researchers design the guide RNA (gRNA) to specifically target the mutated sequence in the HBB gene. They also prepare the CRISPR-associated protein 9 (Cas9) enzyme that will cut the DNA at the targeted location.
- Delivery into Cells: The CRISPR components (gRNA and Cas9) are delivered into the patient’s hematopoietic stem cells, which are the cells responsible for producing blood cells, including red blood cells.
- Editing the Genome: The guide RNA guides the Cas9 enzyme to the mutated region in the HBB gene, where the Cas9 makes a precise cut. The cell’s natural repair machinery then kicks in.
- Repair Mechanism: The cell’s repair machinery may use the provided template or the non-homologous end joining (NHEJ) repair pathway to fix the cut in the DNA. Ideally, if a template is provided, the corrected sequence from the template is incorporated into the genome, replacing the mutated sequence.
- Production of Healthy Hemoglobin: The corrected cells, now with a properly functioning HBB gene, can produce normal hemoglobin instead of the abnormal hemoglobin characteristic of sickle cell disease.
- Transplantation: The edited hematopoietic stem cells are then reintroduced into the patient through a stem cell transplant. The hope is that these edited cells will give rise to healthy blood cells, including red blood cells with normal hemoglobin
The treatment has worked for the majority of the patients that have undergone the trial and there are no short term negative implications on the patients. The first patients of this treatment claim that it has positively changed their lives. Victoria Gray, age 38 is among the first patients to receive CRISPR treatment and she claims that it completely changed her life for the better. Prior to the treatment Victoria’s life had become a series of unfinished chapters as she could barely finish school, take care of her children and hold a stable job because her symptoms crippled her. After the treatment all her symptoms disappeared and it was as if she had never been sick and she now champions for the approval of the CRISPR treatment as it will help change the lives of many sickle cell patients just as it changed hers.
This technique provides a solution for many patients and it is advantageous in that there will be no worry over compatibility with donors because the bone marrow will be extracted from the patient to obtain the cells that need editing so as to eradicate the disease. There will be no need to give the patients immunosuppressants because these are detrimental to patients as they weaken their immune systems making them susceptible to infections,moreover, the risk of graft vs host diseases is greatly decreased as the graft is obtained from the patients themselves. This disease is common in stem cell transplants where the immune cells from the donor attack the tissues of the recipient causing them immense pain.
References
- Mburu, Joy, and Isaac Odame. 2019. “Sickle Cell Disease: Reducing the Global Disease Burden.” International Journal of Laboratory Hematology 41 Suppl 1: 82–88. https://doi.org/10.1111/ijlh.13023.
- Kuznik, Andreas, Abdulrazaq G Habib, Deogratias Munube, and Mohammed Lamorde. 2016. “Newborn Screening and Prophylactic Interventions for Sickle Cell Disease in 47 Countries in Sub-Saharan Africa: A Cost-Effectiveness Analysis.” BMC Health Services Research 16: 304. https://doi.org/10.1186/s12913-016-1572-6.
- McGann, Patrick T, Léon Tshilolo, Brigida Santos, George A Tomlinson, Susan Stuber, Teresa Latham, Banu Aygun, et al. 2016. “Hydroxyurea Therapy for Children with Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial.” Pediatric Blood & Cancer 63 (1): 98–104. https://doi.org/10.1002/pbc.25705.
- Zhou, Albert E, and Mark A Travassos. 2022. “Bringing Sickle-Cell Treatments to Children in Sub-Saharan Africa.” The New England Journal of Medicine 387 (6): 488–91. https://doi.org/10.1056/NEJMp2201763.
- Le Page, Michael. 2023. “Sickle Cell CRISPR ‘Cure’ Is the Start of a Revolution in Medicine.” New Scientist 260 (3466): 16. https://doi.org/10.1016/S0262-4079(23)02182-6.
- Shyr, David C, Robert Lowsky, Weston Miller, Mark A. Schroeder, Tonia Buchholz, Kirstin Dougall, Allison Intondi, et al. 2023. “One Year Follow-up on the First Patient Treated with Nula-Cel: An Autologous CRISPR/Cas9 Gene Corrected CD34+ Cell Product to Treat Sickle Cell Disease.” Blood 142: 5000. https://doi.org/10.1182/blood-2023-188963.
- Vida Ebrahimi, and Atieh Hashemi. 2021. “The Fabulous Impact of CRISPR Method in Sickle Cell Disease Treatment.” Trends in Peptide and Protein Sciences 6: 1–8. https://doi.org/10.22037/tpps.v6i.34202.
- Anitra Persaud, Stacy Desine, Katherine Blizinsky, and Vence L. Bonham. 2018. “A CRISPR Focus on Attitudes and Beliefs toward Somatic Genome Editing from Stakeholders within the Sickle Cell Disease Community.” Genetics in Medicine. https://doi.org/10.1038/s41436-018-0409-6.
- Camille Castelyn. 2021. “Shifting Perceptions of CRISPR.” Voices in Bioethics 7. https://doi.org/10.52214/vib.v7i.8595.
