I have just added a new blog on important new research on this topic. I hope this proves of interest.

First Approval for Use of Gene Editing for the Treatment of Haemoglobin Disorders

I previously blogged about the exciting development of the new technique of gene editing for the treatment of sickle cell disease (Gene Editing for the Treatment of Sickle Cell Disease. 1^st March 2022). In a world first, the UK Medicines Regulatory Agency has now approved this procedure. This approval also covers use in the related disease of β-thalassaemia.

Both conditions are inherited diseases affecting the production of the blood protein β-haemoglobin. They are comparatively common in people whose ancestry arose in the Mediterranean, Middle East, Africa or Asia. The explanation is that these regions, at least historically, where affected by malaria. Although the mutations causing sickle cell disease and β-thalassaemia are harmful under normal conditions, they do give some protection from malaria.

These two disease cause a great deal of suffering. Current treatment options for both conditions are limited and cannot fully protect from long term complications, so patients face shortened life expectances.

The new gene editing treatment uses the recently developed editing tool CRISPR which enables pin-point changes to be made in a single gene. The discovery of CRISPR was awarded a Nobel Prize in 2020.

The licenced treatment, called Casgevy, involves taking a sample of the patient’s own bone marrow stem cells, and modifying them by CRISPR. The patient’s remaining bone marrow cells are then depleted, and the gene edited cells are returned. The patient is likely to need a hospital stay of a month in a protected ward while the modified bone marrow regenerates to full activity. It is therefore not an easy treatment, nor does it come cheap. But set against it are the considerable costs of the current management and treatment of these conditions. Since it is only bone marrow cells which receive the gene editing, the edit will not be passed on to any children the patients may have after treatment.

Casgevy takes a subtle approach to tackling these diseases because it does not target the faulty β-haemoglobin gene directly. Instead it targets a controlling gene called BCL11A. In adults the β-haemoglobin chain is a major component of haemoglobin, the oxygen carrying protein. But in the foetus a further chain, γ, is found in its place: there is a γ to β switch at birth. It has long been known that those few individuals with sickle cell disease or β-thalassaemia who persist in producingγ beyond birth are spared the worst effects of these diseases. Some years ago it was discovered that the γ to β switch is controlled by the BCL11A gene. Casgevy disrupts BCL11A to block the switch away from γ, allowing its production to continue. thereby ameliorating the effects of the faulty β gene.

Of the 70 or so patients treated by Casgevy and followed up for a 12 month period, over 90% were free of disease episodes and had no need for additional treatment. This apparent cure represents a step change in their clinical management. They will continue to be monitored to find out how long these cures last.  Also, although CRISPR is a very precise gene editing tool, does there remain a risk, however small, of it hitting the wrong target in the DNA? Given the marked benefits of Casgevy for these patients it seems a risk worth taking, but due to the extreme novelty of this approach, this needs to be monitored this carefully.

Following this first approval for the medical use of CRISPR can we look forward to more approvals for its use in other genetic diseases?

© CC Rider

29th Dec 2023

I previously blogged about the exciting development of the new technique of gene editing for the treatment of sickle cell disease (Gene Editing for the Treatment of Sickle Cell Disease. 1^st March 2022). In a world first, the UK Medicines Regulatory Agency has now approved this procedure. This approval also covers use in the related disease of β-thalassaemia.

Both conditions are inherited diseases affecting the production of the blood protein β-haemoglobin. They are comparatively common in people whose ancestry arose in the Mediterranean, Middle East, Africa or Asia. The explanation is that these regions, at least historically, where affected by malaria. Although the mutations causing sickle cell disease and β-thalassaemia are harmful under normal conditions, they do give some protection from malaria.

These two disease cause a great deal of suffering. Current treatment options for both conditions are limited and cannot fully protect from long term complications, so patients face shortened life expectances.

The new gene editing treatment uses the recently developed editing tool CRISPR which enables pin-point changes to be made in a single gene. The discovery of CRISPR was awarded a Nobel Prize in 2020.

The licenced treatment, called Casgevy, involves taking a sample of the patient’s own bone marrow stem cells, and modifying them by CRISPR. The patient’s remaining bone marrow cells are then depleted, and the gene edited cells are returned. The patient is likely to need a hospital stay of a month in a protected ward while the modified bone marrow regenerates to full activity. It is therefore not an easy treatment, nor does it come cheap. But set against it are the considerable costs of the current management and treatment of these conditions. Since it is only bone marrow cells which receive the gene editing, the edit will not be passed on to any children the patients may have after treatment.

Casgevy takes a subtle approach to tackling these diseases because it does not target the faulty β-haemoglobin gene directly. Instead it targets a controlling gene called BCL11A. In adults the β-haemoglobin chain is a major component of haemoglobin, the oxygen carrying protein. But in the foetus a further chain, γ, is found in its place: there is a γ to β switch at birth. It has long been known that those few individuals with sickle cell disease or β-thalassaemia who persist in producingγ beyond birth are spared the worst effects of these diseases. Some years ago it was discovered that the γ to β switch is controlled by the BCL11A gene. Casgevy disrupts BCL11A to block the switch away from γ, allowing its production to continue. thereby ameliorating the effects of the faulty β gene.

Of the 70 or so patients treated by Casgevy and followed up for a 12 month period, over 90% were free of disease episodes and had no need for additional treatment. This apparent cure represents a step change in their clinical management. They will continue to be monitored to find out how long these cures last.  Also, although CRISPR is a very precise gene editing tool, does there remain a risk, however small, of it hitting the wrong target in the DNA? Given the marked benefits of Casgevy for these patients it seems a risk worth taking, but due to the extreme novelty of this approach, this needs to be monitored this carefully.

Following this first approval for the medical use of CRISPR can we look forward to more approvals for its use in other genetic diseases?

© CC Rider

A 5-month old baby boy called Arthur, diagnosed with the devastating condition of spinal muscular atrophy, has become the first patient to be treated in the United Kingdom by the National Health Service with a new gene therapy.

Spinal muscular atrophy, SMA for short, affects around 1 in every 10,000 births and is the result of mutations in a gene called SMN1. It is an inherited disease and babies born with it have mutations in both of their copies of the SMN1 gene. The absence of a functional SMN1 gene means they cannot make the corresponding protein.

Their parents will be healthy carriers with one normal SMN1 gene and one mutant copy, and it is this mutant copy which they will both have passed on to their affected child. In the parents, the single normal copy of the gene means that they are able to make the SMN protein in their cells, so they are unaffected. Around 1 in 50 of the population have a single SMN1 gene mutation and will be unaware of it, unless they have children with someone who also has such a mutation. Even then, their children have only a 1 in 4 risk of suffering from SMA. So nearly all the SMN1 gene mutation carriers in the population will be quite unaware of the danger to their children lurking in their mutated version of this genes. There is unlikely to be any family history of this condition amongst their relatives.

The affected children, lacking a normal functional SMN1 gene, are unable to make the SMN protein. Its absence causes the motor nerve cells emerging from their spinal columns to begin to die. These are the cells which control the movement of muscles, and as they die the muscles become progressively unresponsive and weaker. Babies with the most serious form of SMA face a short and limited existence. These babies are unable to sit up, and lose the ability to move their limbs and heads. Eventually the muscles needed for breathing begin to fail, and very sadly these children are unlikely to survive until their 3^rd birthdays.

In 2019, the US Food and Drug Administration approved a gene therapy developed by Novartis for use in babies with severe SMA. Other jurisdictions have now followed suite. This involves infusing the children with a harmless virus modified to carry a normal copy of the SMN1 gene. Once these viruses have entered the baby’s cells, the SMN protein can be made, and the motor nerve cells will cease dying. Nearly all of the children in the clinical trials of this gene therapy have shown benefits, being able to breathe unaided at 14 months of age, and with a half of them able to sit independently at 18 months. Some treated children have reported even better responses. At present is too soon to be able to report the long-term outcomes of this treatment.

Now that we have an effective, if highly expensive treatment, it is important to diagnose SMA children as early as possible. Usually they are diagnosed at around  3 months of age onwards, when they fail to achieve the normal developmental milestones in mobility, such as reaching to grasp objects. The issue here is that once an affected child has been born, motor nerve cells are being lost steadily, and they cannot be replaced. A number of countries already use a genetic test to screen all babies at birth for SMA, and the pressure is now on for this to be adopted more widely, so as to maximise the benefits of this new gene therapy.

©CC Rider

2^nd Jun 2021

A Mutated Gene Which Causes Cancer

The adult human body is estimated to contain a total of 37 trillion cells. We have all arisen from a single fertilised cell by many rounds of cell division, giving firstly 2, then 4, then 8, then 16 cells and so forth. Once we have reached adult size, cell division is then tightly regulated to maintain the correct number of cells at the appropriate anatomical site. Any remaining cell division is balanced to only replace worn out or damaged cells. In cancer this tight regulation goes awry.

Cancer arises from damage to our DNA which results in a particular cell type undergoing continuous and uncontrolled cell division. In this way an excess of unnecessary and unwanted cells accumulates in the body. Over the last 50 years or so, cancer research has revealed that it is mutation in certain specific genes which drives the development of cancers. These genes are called oncogenes.

One instance of such genes are the set of three which carry the instructions to make normal variants of a protein called Ras. The Ras proteins act as signalling switches within our cells. Cells from time to time receive activating signals from within the body. When these become strong and prolonged, they can trigger the cell to start dividing and to become highly active. Ras has a role in transmitting such signals from the outside of the cell to its central nucleus, in which all our genes are stored.

Normally Ras flickers on and off according to these signals, as its structure is switched rapidly between active and inactive states, rather like a controlling circuit within a complex electronic device. However there are certain tiny errors,  or mutations, which can occur within the Ras genes. Some of these then cause the Ras proteins they produce to be permanently locked into the ‘on’ state. If this happens, the signalling circuit which Ras participates in is permanently active and the cell is driven to undergo cell division without ceasing, producing more and more overactive cells.

Ras mutations are found in around one quarter of all human cancers, although the proportion varies greatly from one cancer type to another. For instance some 90% of pancreatic cancers  contain mutations in a Ras gene, whereas other cancers show very little. With modern gene sequencing techniques, it is straight forward to find out whether the cancer in an individual patient has the Ras mutations, or not.

Cancer researchers are now trying to find ways of switching off excess Ras signalling in those cancers containing these mutations, but the challenge of being able to do this effectively and safely has so far proved elusive.   

Ras is just one of several well-established oncogenes which can cause cancer when they are mutated.

©CC Rider

Tocilizumab – a new Covid-19 drug obtained through genetics

Last week, almost buried by the latest positive announcements on Covid-19 vaccines, was the good news of a successful drug trial.  Tocilizumab, a drug used for the treatment of severe arthritis, has been shown to more than halve the death rate in hospitalised patients with severe Covid-19 pneumonia.

In severe Covid-19 infections, over-activity of the patient’s immune system presents a danger to their survival, so doctors have been looking for ways to damp down this excessive response. The anti-inflammatory steroid, dexamethasone, was the first drug shown to have positive effects in this way. Now tocilizumab, which has previously been used to reduce immune over-activity in rheumatoid arthritis has been proven to benefit patients with severe Covid-19.   

Tocilizumab works in a completely different way from dexamethasone.  It specifically targets and blocks a protein on a major activation pathway which normally acts to trigger immune reactions.  By blocking this particular protein, immune activation is reduced. So what does this have to do with genetics?

Well firstly, like many proteins in the immune system, the targeted protein could only be identified by first finding its gene.  Secondly, once this gene hunting was successful, genetic engineering within research laboratories was needed to study the properties of this protein, and to raise an antibody which would recognise it specifically.   

Finally, this antibody was initially generated in a laboratory mouse, so it is a mouse-derived antibody.  As a foreign antibody it will not work well once administered into patients.  The patient’s immune system will start to neutralise and remove it. To avoid this, more genetic engineering is needed to snip out the small elements of the antibody which actually bind to the target and graft them into a human antibody backbone.  Such an antibody is now mostly of human origin and is therefore referred to as a humanized antibody.

Increasingly some our new important and most powerful medicines are humanized antibodies, for use in the treatment of serious diseases including rheumatoid arthritis and cancer.

In the case of tocilizumab, it still needs licence approval for use in severe Covid-19 infection, but since there is much clinical experience of its use in rheumatoid arthritis, this should be a straight-forward process. We can therefore be confident that we now have a new brick in the wall of our defences against the coronavirus.

©CC Rider

23^rd Nov 2020

Tocilizumab – a new Covid-19 drug obtained through genetics

Last week, almost buried by the latest positive announcements on Covid-19 vaccines, was the good news of a successful drug trial.  Tocilizumab, a drug used for the treatment of severe arthritis, has been shown to more than halve the death rate in hospitalised patients with severe Covid-19 pneumonia.

In severe Covid-19 infections, over-activity of the patient’s immune system presents a danger to their survival, so doctors have been looking for ways to damp down this excessive response. The anti-inflammatory steroid, dexamethasone, was the first drug shown to have positive effects in this way. Now tocilizumab, which has previously been used to reduce immune over-activity in rheumatoid arthritis has been proven to benefit patients with severe Covid-19.   

Tocilizumab works in a completely different way from dexamethasone.  It specifically targets and blocks a protein on a major activation pathway which normally acts to trigger immune reactions.  By blocking this particular protein, immune activation is reduced. So what does this have to do with genetics?

Well firstly, like many proteins in the immune system, the targeted protein could only be identified by first finding its gene.  Secondly, once this gene hunting was successful, genetic engineering within research laboratories was needed to study the properties of this protein, and to raise an antibody which would recognise it specifically.   

Finally, this antibody was initially generated in a laboratory mouse, so it is a mouse-derived antibody.  As a foreign antibody it will not work well once administered into patients.  The patient’s immune system will start to neutralise and remove it. To avoid this, more genetic engineering is needed to snip out the small elements of the antibody which actually bind to the target and graft them into a human antibody backbone.  Such an antibody is now mostly of human origin and is therefore referred to as a humanized antibody.

Increasingly some our new important and most powerful medicines are humanized antibodies, for use in the treatment of serious diseases including rheumatoid arthritis and cancer.

In the case of tocilizumab, it still needs licence approval for use in severe Covid-19 infection, but since there is much clinical experience of its use in rheumatoid arthritis, this should be a straight-forward process. We can therefore be confident that we now have a new brick in the wall of our defences against the coronavirus.

©CC Rider

23^rd Nov 2020

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