What causes Sickle Cell Disease & the Symptoms
The substitution of thymine to adenine on the sixth codon of the genetic sequence alters the physical properties of the haemoglobin, giving them the characteristic crescent shape. This abnormality makes them inflexible, therefore they can hemolyse, form blockages by forming rigid polymers that cause chronic anemia, and inflammation. One of the main symptoms is Anemia, this is caused by the sickled red blood cells (RBC) breaking apart at a faster rate than healthy cells, therefore less oxygen.
Damage to the spleen (responsible for the filtration of blood, removing old or damaged blood cells), which causes frequent infection because there is a reduced number of white blood cells. Another common symptom is jaundice, a byproduct from the breakdown of haemoglobin, bilirubin, is yellow coloured so when in excess it causes yellowed skin and eyes. Also swollen hands and feet can be a sign of SCD because the small blood vessels in extremities can be blocked from sickled cells, causing fluid to be trapped.
Current Treatments
The vast majority of treatments prioritised improving the symptoms caused by SCD as opposed to preventative measures, such as Hydroxyurea or L-glutamine. Hydroxyurea is taken orally, reducing the need for blood transfusions and improving anaemia because it lowers the WBC -less pain crises due to reduced inflammation- as well as increasing fetal haemoglobin production. L-glutamine reduces the oxidative stress (too many free radicals damaging the cells), so it makes sickled cells less fragile and likely to break apart . Though it's important to make the distinction that L-glutamine does not change the type of haemoglobin unlike Hydroxyurea.
Gene Editing: Casgevy
Vertex Pharmaceuticals developed a product called Casgevy, which uses CRISPR-Cas9 as a foundation to reactive fetal haemoglobin production in faulty cells. This prevents red blood cells from sickling, ensuring that red blood cells remain flexible and can efficiently transfer blood into respiring muscle cells. Essentially, Casgevy uses the exact CRISPR-Cas9 mechanism, however it is repurposed to be specific for sickle cell or β-thalassemia. The main components of the CRISPR sequence are: protospacer adjacent motifs (PAM), cRNA, and tracrRNA. Protospacer adjacent motifs are short DNA sequences which have been incorporated into the locus. They are vital to the whole system because their presence at the end of a sequence facilitates a double strand break. PAMs are a few nucleotides down from targeted sequence so that the cas nuclease is only able to cut the specific gene. TracrRNA, regulates gene expression on different genomic loci because they are complementary to the palindromic repeats. Cas9 Nuclease, is what initiates the double strand break of the DNA at a chosen location. Then protospaces are used because Casgevy is targeted to SCD, this is located in the BCL11A⁴ erythroid enhancer region. This is targeted because BCL11A inhibits fetal haemoglobin (HbF) after birth, and higher HbF levels protect against sickling because it cannot be polymerised into rigid shapes
How it Works
The patient is given a mobilization treatment, this allows stem cells to move into the blood from the bone marrow, they are collected through a process called apheresis. Up to six months can be taken for the patient’s cells to be tested with CRISPR and manufactured to produce RBC with a high level of HbF. Once completed the patient is given a condition medicine which clears cells from bone marrow. This is crucial because it gives sufficient space for the modified cells. Because blood levels will fall to an extremely low level, the patient is monitored closely in the hospital for a few days. Then Casgevy will be administered through intravenous infusion. Cas9 and the sgRNA will work as a duplex to target the BCL11A gene with unprecedented accuracy, the erythroid-specific enhancer is targeted and disrupts the region by cutting through the gene, eliciting small deletions at the site. Now there will be an increased production of fetal haemoglobin.
Out of 71 patients, 67 were free from acute pain after a year and no severe side effects were recorded. Casgevy using human cells makes it significantly safer as it is not a foreign object inserted, setting it apart from other novel treatments which carry that risk. Also, Casgevy has been approved both in the USA by the FDA and in the UK, further solidifying its safety and innovative nature.
References
1) Smith, Y. (2021) ‘Sickle Cell Disease Pathophysiology’, News Medical Life Science, 27 Mar. Available at:https://www.news-medical.net/health/Sickle-Cell-Disease-Pathophysiology.aspx (Accessed: 17 Aug 2025)
2) Safety and Side Effects of CASGEVY’, Casgevy. Available at: https://www.casgevy.com/sickle-cell-disease/safety-side-effects (Accessed: 17 Aug 2025)
3) Smith, Y. (2022) ‘What is Sickle-Cell Disease?’, News Medical Life Science, 17 Jan. Available at: https://www.news-medical.net/health/What-is-Sickle-Cell-Disease.aspx (Accessed: 17 Aug 2025)
4) Gostimskaya, I. (2022) ‘CRISPR-Cas9: A History of Its Discovery and Ethical Considerations of Its Use in Genome Editing’, PubMed, 15 August. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC9377665/ (Accessed: 17 Aug 2025)
5) Adebiyi, M. (2023) ‘Importance of the PAM sequences in CRISPR-Cas9 gene editing’, Integrated DNA Technologies, 12 December. Available at:https://eu.idtdna.com/pages/education/decoded/article/importance-of-the-pam-sequences-in-crispr-cas9-gene-editing (Accessed: 17 Aug 2025)
6) ’CASGEVY is a CRISPR/Cas9-modified autologous CD34+ cellular gene therapy’, Casgevy.Available at: https://www.casgevyhcp.com/sickle-cell-disease/mechanism-of-action# (Accessed: 17 Aug 2025)
7) ‘Casgevy - how it works’, NHS, 8 Dec. Available at: https://www.genomicseducation.hee.nhs.uk/blog/casgevy-how-it-works/ (Accessed: 17 Aug 2025)
8) ‘FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease’, FDA, 8 Dec. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease (Accessed: 17 Aug 2025)