ZOLGENSMA™ is the trademark name for Onasemnogene abeparvovec. It is manufactured by the pharmaceutical company Novartis Gene Therapies.

Zolgensma is a gene therapy that delivers a healthy copy of the SMN1 gene to motor neurons. It is made from parts of a virus called AAV9 (adeno-associated virus 9). It transports SMN1 around the body to many different cells, helping to restore some of the SMN protein that is missing in SMA.

AAV9 cannot produce copies of itself and is therefore unable to be passed from person to person. It is only used to treat 5q variant spinal muscular atrophy (5q SMA).

Zolgensma is injected into the bloodstream (intravenously). A small flexible tube (cannula) is placed into a vein in the arm or leg using a needle. The needle is then removed leaving the cannula in place for the infusion.

Since 2014, there are published data from clinical trials in humans where this method of delivery has been used with children treated up to 2 years of age. Several trials of Zolgensma in a wider range of children who have SMA are currently ongoing, including those who are older and heavier than in the initial trials.

Novartis Gene Therapies was also conducting clinical trials to see whether intrathecal administration of Zolgensma (i.e., directly into the fluid bathing the spinal cord and brain) would address the needs of those who are older than 2 years. These were put on hold, but were started again in August 2021. This is the STEER trial.

To create a gene therapy, components of a virus are used. This is because viruses have a natural ability to travel around the body once they gain access. However, most viruses can also replicate themselves to produce many copies.

That is why gene therapies only include the parts of a virus that allow it to travel around the body. They do not include the parts that allow it to replicate.

Zolgensma is made from harmless parts of the AAV9 virus, which has been ‘gutted’. This creates something like an empty envelope that can have something inserted. As the purpose of Zolgensma is to increase SMN protein, the SMN1 gene is put into the empty AAV9 envelope.

When introduced into the blood, Zolgensma is able to travel through the bloodstream and reach the brain and motor neurons. It delivers SMN protein to where it is needed.

Viruses are usually combated by our immune systems. For example, we may initially suffer after contracting a flu virus, but when our immune system starts to work, we fight the virus and get better. After exposure to a particular virus, our bodies produce proteins called antibodies that will very specifically recognise and neutralise that same virus in the future.

When this happens, we are said to have developed an immunity to that particular virus. This will help to prevent us from becoming ill again.

Our immune system responds to parts of AAV9 virus used in Zolgensma in the same way as to a flu virus. As soon as Zolgensma is introduced into a child, their body starts to produce antibodies against it. Despite this, Zolgensma can still produce the required SMN protein.

If a child were to have a second injection of Zolgensma, it would not work, as they will have developed an immunity to it. This means that only a single injection of the treatment can be effectively used.

The AAV9 virus that is used to create Zolgensma is naturally found in the environment. This means that some children, including children with SMA, will have developed an immunity to AAV9. They will therefore not benefit from Zolgensma.

Children being considered for treatment with Zolgensma will first have their blood tested to see if they have this natural immunity. This is the AAV9 antibody test. If they show a response, they are unlikely to benefit from Zolgensma and are therefore ineligible for treatment.

In June 2021, Novartis Gene Therapies told us:

"A small number of children may have developed AAV9 antibodies before they are tested.  The presence of these antibodies could mean that it is not possible to administer zolgensma. This depends on what is called the ‘antibody titre level’. If AAV9 antibody titres are reported to be above 1:50, your child may be re-tested. AAV9 antibody results are valid for 30 days."

Recent evidence suggests that only a small number of children may become ineligible for this reason (around 5 in 100 children tested)."

Any drug, including ones that are commonly prescribed or sold over the counter, may cause possible side effects. Side effects of medications are reported and recorded during their clinical trials. They are also picked up through the ongoing systems that are in place to monitor medications and their use in the ‘real world’.

All possible side effects are listed in the Patient Information Leaflet that is given with any medication. They are grouped as:

• very common
• common
• uncommon
• rare.

For Zolgensma, possible side effects listed are:

Very common: may affect more than 1 in 10 people

• increases in liver enzymes seen in blood tests.

Common: may affect up to 1 in 10 people

• vomiting
• fever.

An infection (e.g., cold, flu or bronchiolitis) before or after Zolgensma treatment may lead to more serious complications.

These and any rare or very rare side effects are listed in Novartis Gene Therapies’ Patient Information Leaflet . This covers other questions as well (see Q 10 below).

Professor Muntoni, Consultant Neurologist at Great Ormond Street Hospital (GOSH), has told  us:

"No, they only have a similar name because one is an adeno viral vector, the other is an adeno-associated viral vector/ Although the names look similar, they are not even like cats and dogs, they are even more different ones. So, no there is no problem."

Zolgensma is a gene therapy that has been engineered to contain the SMN1 gene. Once Zolgensma has been injected, it travels around the body. It reaches the body’s cells and increases the amount of SMN protein that they can produce. Increasing SMN in this way, can counteract some of the negative effects caused by the low amount of this important protein. However, zolgensma is not a cure:

Timing is critical. Although the treatments can rapidly increase SMN protein production after administration, some irreversible damage may have already occurred in the nervous system. This may happen even before a baby is born.

It is not known whether any of the treatments will have continuing effects as they are all so relatively new (see clinical trials information).

No, they will not pass on the new healthy SMN1 gene.

Zolgensma gene therapy does not integrate into the DNA of human cells. This is what makes Zolgensma safe to use. If it were to insert itself into DNA, it could disrupt the function of healthy genes and cause them to malfunction.

Importantly, Zolgensma also does not integrate into the DNA of reproductive cells known as the “germline” (e.g., sperm/egg cells). This means that the healthy SMN1 gene that has been engineered into Zolgensma cannot be passed on to the next generation.

In May 2020, the European Commission approved dosing guidance for  Zolgensma to cover babies and young children who have SMA up to 21 kg.

One of the challenges for Zolgensma is the increased potential risk of children who are heavier. They need an increasingly large viral load to deliver an effective treatment. Clinicians and researchers know from experience of other clinical trials that this increased viral load could in itself create some severe side effects and outcomes.

 In the UK there was on investigation into Zolgensma safety concerns 9th January – 28th March 2023. These were resolved.

• Why the UK programme was paused for children aged over 12 completed months
• SMA Community submission to the MHRA
• Why the Pause was Lifted

Novartis’ global clinical trial of Zolgensma called SMART is following up 24 patients weighing between 8 and 21 kgs.

Yes, results from an observational study of the efficacy and safety of Zolgensma were published in the Lancet medical journal in October 2021. These included children older than 24 months at treatment who had previously received nusinersen.  Read the study report.

You will find the answer to many of your questions in Novartis Gene Therapies’ Patient Information Leaflet. You can discuss any further questions you may have with your or your child’s clinician. The leaflet covers:

1. What Zolgensma is and what it is used for

2. What you need to know before your child is given Zolgensma

3. How Zolgensma is given

4. Possible side effects

5. How to store Zolgensma

6. Contents of the pack and other information

There are now three drugs funded by the NHS for people who have SMA. Until 2018 there were none. Different eligibility criteria apply to each one.

There have been no studies to date that directly compare the treatments. You will be able to discuss treatment options with your clinical team. Together you will be able to discuss the risks and benefits of any of the treatments that are potentially possible. You will be able to make an informed decision as to which one is best for you or your child.