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Gene Therapy for Babies with Severe Spinal Muscular Atrophy

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 3rd 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

2nd 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

2nd Feb 2021

Genes and Severe Covid-19

The Covid-19 virus has varying effects on different people. Many people experience no noticeable symptoms and their infections will only be revealed should they undergo a Covid-19 test. Others may experience just moderate symptoms which pass in a few days. However the real problem lies within the group of individuals who develop life-threatening respiratory disease. This is highly distressing and can even prove fatal, especially in the elderly, or those with pre-existing heart or lung conditions. Why is there such a very broad spectrum of response to Covid-19 infection? One interesting possibility is that disease severity may depend on the amount of virus someone is infected with. But another possibility is that some people have a genetic pre-disposition to respond badly to Covid-19.  

It is this last possibility which has been investigated by a large international research group led by Dr J K Baillie in Edinburgh. This team scanned the entire genomes of 2244 patients who are in UK intensive care wards with severe Covid-19. They then performed computer searches which compared the frequency of gene variants within this group to those occurring amongst a large control group in the extensive UK genome database. They next verified their findings on a further group of 2415 severe Covid-19 patients. This work enabled them to identify 4 genome regions with particular gene variants found more often in the severe Covid-19 groups. To this another gene was added which does not have a variant DNA sequence, but which is expressed at higher levels in the Covid-19 sufferers compared to the normal population.

By knowing the individual genes involved in these variations it is possible to group them into two classes. One of these classes is involved in the very early responses to virus infection. Because such responses will have come into play several days before a patient develops severe Covid-19, there is little prospect that medical interventions here will be of benefit.

However the second class of genes control inflammatory responses, and it is dangerous over-reaction of on-going inflammatory responses in the lung which is the problem in severe Covid-19. Here there is hope that the new research has identified a new target suitable for clinical treatment. One gene in this second class is called Tyk2 (pronounced as tyke two) and this encodes an enzyme which drives prolonged inflammatory responses. The Tyk2 gene variant identified in severe Covid-19 causes too much Tyk2 enzyme to be produced. Excitingly, there is already a drug called baricitinib which is used to inhibit Tyk2 in the treatment of rheumatoid arthritis, another disease of excessive inflammation, in this instance in the joints rather than the lungs. Since baricitinib is already in clinical use, we already have a full knowledge of its safety profile and suitable dosage levels. Now we just need a clinical trial in severe Covid-19 to find out whether baricitinib does actually save lives and might speed the recovery of a patient who is in a very ill state in intensive care. If it does, it will not only provide a huge benefit, but it will also become a great example of how advanced genetics can provide improvements in medical care.   

©CC Rider

14th Dec 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

23rd Nov 2020

What is an RNA Vaccine?

Congratulations to Pfizer and BioNTech on the successful interim results of their RNA vaccine against Covid-19.  It is an extraordinary achievement to have reached this stage within some 10 months, when normally developing a vaccine this far would take around 10 years. This new candidate vaccine is a novel type of vaccine, being an RNA vaccine.  Such vaccines have only been possible in recent years, resulting from advances in genetics.  But what is an RNA vaccine, and how do they work?

Most people will be aware that the genes of living organisms, including humans, exist as DNA, or to give it its full chemical name deoxyribonucleic acid. This formal name arises from the fact that its backbone is made up of the sugar, deoxyribose.  This is derived from the more usual sugar ribose by removing an oxygen atom from it, hence deoxyribose.

When a gene becomes active, it is copied out as a strand of RNA, in full, ribonucleic acid. RNA is very similar to DNA, but its name is due to a key chemical difference. Its backbone is made from normal ribose, not deoxyribose.  This RNA version of the gene then directs the production of multiple copies of the encoded protein.

Many viruses, including Covid-19, do not have DNA.  Instead the few genes they possess are in the form of RNA. When such viruses infect a cell, they release their RNA, which then hijacks the cell into making lots of the different viral proteins from which new virus particles can be assembled.

An RNA vaccine mimics this process but in a limited way.  An artificial RNA encoding just a single virus protein is produced.  Upon injection, this artificial RNA enters some of the recipient’s cells where it makes just the single encoded protein. The process is inherently safe because the other Covid-19 genes are absent, so the other proteins the virus needs cannot be made.  Instead the single Covi-19 protein appears on the surface of the recipient’s cells.  There it will be detected by the recipient’s immune system as a ‘foreign’ i.e. non-human protein.  An immune response will then be triggered.  This means that should, at a later time, the recipient encounter Covid-19, they will be protected from it.

One point should be made clear.  Just because this is a RNA vaccine, and RNA is closely related to DNA, it cannot alter our own DNA, and so will not change our genetic make-up.  In time the vaccine will be eliminated from our cells.

There are a number of hurdles to be overcome before this new vaccine can be licensed, and since this is a new type of vaccine, the authorities regulating the use of medicines will be especially vigilant. Another issue is that since RNA is not very stable, the vaccine will have to be stored and transported at very cold temperatures (-70o C).  This raises complications in delivering it to clinics for use.

Nonetheless this vaccine candidate gives some hope at the end of the long and dark Covid-19 tunnel.

©CC Rider

12th Nov 2020


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