THE START OF AN EXCITING NEW ERA –
GENE THERAPY TREATMENT FOR PEOPLE LIVING WITH SICKLE CELL
By Mary Clarke
Most of us know someone with Sickle Cell Disease (SCD) either a family member or as a friend or you yourself may be living with Sickle cell
Sickle Cell is a genetic disorder which has a significant impact on the life of those who inherit the sickle gene.
The exciting news is that there is now hope for a cure for Sickle, with the launch of a revolutionary new gene-editing treatment, that could change everything about living with Sickle cell.
What is Sickle Cell Disease (SCD)?
Sickle cell disease is caused by a small genetic error on the DNA which gives the instructions for making haemoglobin. Haemoglobin is a protein that carries oxygen in red blood cells. This genetic error may be small but the impact is huge, causing episodes of severe pain often needing hospital treatment and organ damage.
What is DNA?
DNA is the set of instructions inside every cell in the body which tells each cell how to make proteins special to that cell. These proteins are the building blocks that makes us. So, DNA is the recipe book or instructions for each of the proteins we need! Haemoglobin is one of these proteins. If the instructions in the DNA for haemoglobin are incorrect, it can result in disorders such as sickle cell or thalassaemia.
How does the sickle gene in the DNA affect the red blood cells?
The sickle gene changes the DNA instructions for making haemoglobin in the red blood cells. This causes the red cells to become rigid and ‘banana shape’ instead of being soft and donut shaped. The rigid red cells get stuck in small blood vessels and so fail to do their job of delivering oxygen. This lack of oxygen can lead to episodes of severe pain and damage to organs.
What treatments are available for Sickle Cell Disease now ?
Bone marrow transplant (stem cell transplant) from a donor
This is the one treatment which can CURE Sickle Cell Disease at the moment. The problem is that a bone marrow transplant needs a matched donor and this usually needs to be a brother or sister. Not many people have a good matched donor so few are done each year.
Blood transfusions
Some of the symptoms and damage caused by SCD can be reduced by blood transfusions. Although these are very effective, they are not a cure. Another challenge is that it needs many generous blood donors and more are required to meet the needs of people with SCD
Hydroxycarbamide/ hydroxyurea
Hydroxycarbamide tablets are another effective treatment but have to be taken regularly and long term and at a high enough dose. Interestingly, one action of hydroxycarbamide is to switch on fetal (baby haemoglobin). You will see that the new gene treatment CASPR-Cas 9 Casgevy also works by switching on fetal haemoglobin – we can do this now but this will be even better.
What is this new breakthrough treatment for Sickle Cell
It is has several names but is one treatment
Casgevy (name given by Vertex the manufacturer)
exagamglogene autotemcel (the scientific name)
Exa-cel( (short scientific name )
What is Casgevy?
Casgevy has been developed using the gene editing technology CRISPR Cas-9 for use specially in sickle cell disease.
How does Casgevy work?
It works by switching on fetal haemoglobin using gene editing technology CRISPR_Cas9. This is going back to what was happening when the person was a baby.
What is so good about fetal haemoglobin?
It is good because Fetal haemoglobin does not sickle
What is CRISPR-Cas9?
CRISPR-Cas9 is a precise and efficient method of modifying DNA
It can cut and then ‘fix’ DNA in a very precise way
It was developed by Jennifer Doudna and Emmanuelle Charpentier and they jointly won the Nobel prize for chemistry in 2020
it has applications in medicine agriculture and biotechnology
What is the connection between Casgevy and CRISPR-Cas9
There are many different versions of CRISPR Cas-9 each of which do different jobs depending on the disease being treated, for example cystic fibrosis, haemophilia and now Sickle Cell Disease and thalassaemia. The newly licenced version of CRISPR-Cas 9 Casgevy is specially made for people with Sickle Cell.
So, what happens in the real world when Casgevy using CRISPR Cas-9 gene editing is given to people with sickle cell?
So far there has only been one study and only a very small number of people treated. In this study 45 patients with severe sickle and no donor, were treated with Casgevy. 29 people could be assessed as they had received the treatment long enough ago to see if it was working. It was found that of these 29 people, 28 had no severe pain episodes in the 12 months since treatment (success of 97%.)
So, what happens in the real world when Casgevy using CRISPR Cas-9 gene editing is given to people with Thalassaemia major?
Casgevy can also be used in transfusion dependant beta thalassaemia major. Similar results were seen with 54 people treated of which 42 were post treatment long enough to be assessed and 39 (93%) were transfusion free. These studies were set up to look at safety and efficacy and the numbers are very small to be completely sure of the results.
Is Casgevy a game changer for sickle cell?
It is a potential cure for life
Only one dose of treatment needed
If widely available it could change lives of millions of people with Sickle Cell and thalassaemia and other genetic disease too
However, it is expensive and complex to deliver and receive
Why is chemotherapy needed before the Casgevy treated stem cells are returned
it is needed to prepare space in bone marrow for the returning cells
How long is spent in hospital after the gene therapy treatment
At least a month in hospital while the modified stem cells grow back and make new blood cells. Intensive follow up occurs for at least one year.
Is everyone eligible for Casgevy?
No, the following are eligibility criteria
Severe sickle cell
Over 12 years old
No donor available
Where will this new treatment Casgevy be given?
Only at specialised centers in
London
Manchester
Birmingham
In summary the treatment with Casgevy
May offer a cure
No donor is needed
It’s a challenging treatment to undergo
Talk with your medical and nursing team
Stay informed so you can make good choices
And finally, a Message from Amanda Prichard Chief executive NHS
“This is a leap in the right direction for people with Sickle Cell disease….it could enable patients to live free from the fear of sickle cell crisis hanging over them”
Further information from these sites may help you
Sickle Cell Society UK
NICE national institute for clinical care and excellence – information about the journey for approval of Casgevy
Centre for evidence-based medicine University of Oxford also has excellent further links
Information from Vertex the maker of Casgevy
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