The Use of CRISPR Gene-Editing to Combat Sickle Cell Anaemia Sickle Cell Anaemia Sickle cell disease is the most common hereditary haematological disorder in the world especially predominant in those of an African

The Use of CRISPR Gene-Editing to Combat Sickle Cell Anaemia Sickle Cell Anaemia Sickle cell disease is the most common hereditary haematological disorder in the world especially predominant in those of an African

The Use of CRISPR Gene-Editing to Combat Sickle Cell Anaemia
Sickle Cell Anaemia
Sickle cell disease is the most common hereditary haematological disorder in the world especially predominant in those of an African, Caribbean, Middle Eastern, and Mediterranean origin 1; the disease is estimated to occur in 0.2% of African Americans and 0.07 to 0.1 % of Hispanic Americans 4. Sickle cell disease is the generic term for a group of inherited genetic disorders that affect red blood cells in the human body ranging from sickle cell anaemia, haemoglobin sickle cell disease, and beta thalassemia. These disorders are known to be the most common inherited conditions in babies born in the UK, where on average 1 in 2,400 new-borns suffer from sickle cell disease 2. Of these, sickle cell anaemia is considered the most common and severe form of sickle cell disease 3.
203200021996400020815304324174Fig.1 Pathophysiology of Sickle Cell Anaemia
00Fig.1 Pathophysiology of Sickle Cell Anaemia
Sickle cell anaemia is an inherited form of anaemia that surfaces following a mutation in the HBB gene, producing abnormally shaped red blood cells. The HBB gene is involved in the production of the protein beta-globin that is a component of a larger protein, haemoglobin, located within red blood cells. A mutant HBB gene results in the production of an abnormal version of beta-globin called haemoglobin S or HbS. Haemoglobin S replaces both beta-globin components within the haemoglobin and this mutation alters the codon of amino acid at position 6 in which the amino acid glutamic acid is replaced with the amino acid valine within the beta-globin. This causes abnormal S components to stick together and form long, rigid molecules that bend red blood cells into a sickle, curved shape 4. These sickle shaped curved cells die prematurely which often leads to a shortage of red blood cells resulting in anaemia and in other cases, the rigid and inflexible structure of the sickle cells can block blood vessels and cause severe pain and organ damage. Sufferers of sickle cell anaemia may experience an increased risk of and vulnerability to infections due to spleen damage, strokes due to the blockage of blood travelling to the brain leading to an oxygen shortage, and acute chest syndrome where the individual may suddenly feel short of breath due to the presence of sickle cells in the lung blood vessels 5. Children may also experience severe episodes of pain and feel lethargic for long periods of time 2.
CRISPR Genome-Editing
CRISPR–Cas9 is an innovative DNA-editing technique that has allowed for the permanent modification of genomes and their function, in human embryos and adults, with an unprecedented precision and flexibility – a high level of accuracy reduces the risk of damage occurring to adjacent genes 5. Genome editing technologies as such provide researchers with the ability to add, remove or alter an organism’s genetic material at certain locations on the genome and CRISPR–Cas9 is proving to be a more efficient and customisable alternative, compared to existing genome-editing methods, with the ability to target multiple genes simultaneously 6. CRISPR is an abbreviation of Clustered Regularly Interspaced Short Palindromic Repeats, which refers to the organisation of short, repeated DNA base sequences in the genomes of bacteria and other organisms 7. CRIPSR has been adapted from a naturally occurring genome editing defence mechanism in bacteria that is activated during a viral attack. This system involves bacteria capturing strips of the invading viruses DNA that the bacteria then splice in their own, using an enzyme called Cas, to create DNA segments known as CRISPR arrays. The bacteria then produce RNA copies of the CRISPR arrays, which enable the bacteria to recognise and instantaneously target the virus and similar viruses in future invasions. The bacteria then use enzyme Cas9 (or a similar enzyme) to split the DNA apart, which disables the virus 8. In 2012 the CRISPR technique enhanced from a bacterial defence into a gene-editing tool and this process involved researchers replacing CRISPR RNA system with a small modified RNA molecule containing a ‘guide’ sequence that binds the specific target DNA sequence in a genome. The RNA also binds to the Cas9 enzyme and this enzyme uses the modified RNA molecule to recognise the DNA sequence and cut the DNA at the targeted location. Researchers then customise the cut DNA using the cell individual DNA repair mechanisms to add or delete fragments of genetic material, or to alter the DNA by replacing an existing segment with a modified DNA sequence 8.

476250603885Fig. 2 CRISPR–Cas9 Gene-Editing Technique
00Fig. 2 CRISPR–Cas9 Gene-Editing Technique

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Currently CRISPR genome editing research involves the use of cells and animal models to allow scientists to enhance their understanding and potentially develop treatments for a variety of diseases that include cancers and hereditary single-cell disorders such as cystic fibrosis and sickle cell disease 8. CRISPR techniques are actively being used to modify pig DNA so that their organs can be transplanted into humans and China have used genome editing in humans to inject cancer-fighting, CRISPR-modified white blood cells into a sufferer of metastatic lung cancer 7. Scientists in China have used genome editing to change the DNA of dozens of patients in several clinical trials and they have genetically engineered the cells of at least 86 cancer and HIV patients using CRISPR-Cas9 technology. There were no scientific reports issued regarding these experiments, but doctors have confirmed that the conditions of some of the patients had improved following gene therapy; yet there have been 15 deaths, 7 of which occurred in one trial, though scientists have confirmed all these deaths to be related to the patient’s previous conditions and not the use CRISPR-Cas9 technology 9. In a clinical CRISPR trial reported by the Wall Street Journal, 36 patients with cancers of the kidney, lung, liver and throat had cells removed from their bodies, altered using CRISPR-Cas9, and then injected back into their bodies to fight the cancer. Other clinical trials conducted in China sought to use CRISPR to treat HIV, oesophageal cancer, and leukaemia. The use of CRIPSR gene editing at an attempt to cure oesophageal cancer involved editing the genome of immune T cells extracted from patient blood to terminate the production of PD-1, a protein that helps cancer cells evade the immune system, then injecting the patient with the modified cells 10; CRISPR genome editing trails as such have also enhanced cancer immunotherapy.

Lab studies from the University of Utah School of Medicine have shown that CRISPR-Cas9 technology can be used to correct sickle cell mutations in experimental and cellular terms. The researchers extracted hematopoietic stem cells from the blood of people with sickle cell disease and using CRISPR gene editing tools, were able to correct the mutations within the stem cell. Following the transplantation of the edited cells into the bodies of those with sickle cell disease, there is expected to be a decline in the in the number and extent of faulty haemoglobin molecules of a sickled shape; however the transplantation stage of the study is yet to be conducted as researchers have to perform large scale tests with mice and lots of safety tests before they are permitted to perform clinical trials on humans. For the gene editing of mutant cells to be effective and useful in the treatment of sickle cell disease the transplanted stem cells must remain alive. To investigate whether this was possible the researchers placed edited hematopoietic stem cells in the bodies of mice to discover that after four months, 2 to 4 percent of the mouse stem cells that were examined were the edited version. Researchers stated that this percentage is too close to the minimum level of survival rate of cells required in humans for the treatment to be deemed beneficial therefore the researchers have decided to focus on increasing the survival rate of stem cells once inserted into the human body before conducting the clinical trial 11.
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