Breakthrough gene therapy gives hope to spinal muscular atrophy patients

Spinal muscular atrophy has long been one of the most serious conditions that affect children, but also one for which treatments have largely been inaccessible.

The neuromuscular disease has often prevented children with the most severe form from reaching their second or third birthday, with little more than palliative care offered to them.

"In terms of treatment, there was nothing," said Tom Gillingwater, a professor of anatomy who researches the disease at the University of Edinburgh in the UK.

However, the situation has improved dramatically thanks to the discovery of treatments that target the genetic make-up of the disease.

Youngsters in the UAE are among those to have benefited, thanks to a new SMA gene therapy treatment offered at Al Jalila Children's Specialty Hospital in Dubai.

A recent paper in Muscle & Nerve outlined how, when the treatment was given to 25 children between late 2020 and early 2022, there were "significant improvements" and only moderate side effects.

This year, UAE residents raised Dh6.6 million ($1.8 million) for a 19-month-old boy to receive the treatment at the hospital.

SMA is a condition that affects the motor neurons (nerve cells that transmit impulses to the muscles) and causes the limbs to be weak.

It makes walking difficult or impossible and creates problems with swallowing, as well as breathing.

Type 1, the most severe form, develops in the first six months of life and, until recently, would typically prove deadly, often due to breathing issues during the early years of life.

Type 2, which develops later, is less severe but may still prevent a child from walking and can cause other disabilities.

Types 3 and 4 cause milder but still significant symptoms and affect older children and adults.

While finding treatment for other neurological conditions such as Alzheimer's or Parkinson's disease has proved difficult, progress has been made with SMA because it has a well-understood genetic basis.

One in 40 to 60 people are a carrier, however, carriers do not have symptoms.

One in four children where both parents are carriers will develop SMA, which equates to one in every 6,000 to 10,000 newborns.

Game-changing treatments

The treatment offered by Al Jalila Children's Specialty Hospital, called Zolgensma, is given once and is a form of gene therapy.

It was approved by the US Food and Drug Administration (FDA) four years ago, and has been described as the most expensive drug in the world, with a single treatment costing about $2 million.

There are two other treatments, also released in the past few years, which also target the genetic factors that cause the disease.

However, those treatments have to be administered numerous times because the replacement gene is not incorporated into the recipient's cells.

It can cost patients hundreds of thousands of dollars a year.

Nusinersen (sold as Spinraza) was approved by the FDA in late 2016. It is injected into the spinal cord and affects a related gene, which in turn enables muscles to function more effectively.

The third drug, risdiplam (sold as Evrysdi) is taken orally and acts in a similar way.

The treatments are "absolutely game-changing" for those affected by SMA, Prof Gillingwater said.

"They have been able to allow children with SMA to live much, much longer and reach real-world milestones," he said.

Success stories

Twins Finn and Zara, five, are among the children to have benefited from Spinraza.

Their father, Giles Lomax, is chief executive of Spinal Muscular Atrophy UK, a charity that provides support for those affected by the condition.

The twins were diagnosed with type 2 SMA in 2019, when they were a year old.

He said it was "really fortunate" that once the twins were diagnosed they were able to start treatment.

Children with type 2 SMA cannot crawl or stand without the help of drugs, and have to use a wheelchair.

However, thanks to Spinraza, Zara can walk, while Finn, although a wheelchair user, can stand, crawl and take a few steps.

"That would never, ever be able to happen without the drugs," Mr Lomax told The National. "That puts them on a very different trajectory.

"There's a lot of children now who have had access to the three drugs that are available and they have, on the large, had a lot of successful stories, some more so than others."

He said many children with Type 1 SMA who were given Spinraza early in life have survived, which would not have been the case otherwise.

"They do have complex needs – they have mobility issues, swallowing issues, feeding issues – but they are here and that's super important," he said.

Early diagnoses is key

Getting an early diagnosis is imperative. However, it is not easy because detecting the condition is based on a child not reaching developmental milestones.

This can vary from child to child and some symptoms mirror those of other conditions.

Organisations such as Spinal Muscular Atrophy UK are now pushing for SMA to be added to the list of conditions for which newborns are screened.

In some cases where treatment has commenced in the early weeks of life, children have been symptom-free.

"As early as possible is key," Prof Gillingwater said.

"If you can treat the child before they have any symptoms, you get remarkably better outcomes."

However, there are some uncertainties around long-term results, as gene-based treatments have only been used for a few years.

There is also "an enormous gap in the understanding" as to why the loss of the survival motor neuron protein results in motor neuron disease, said Simon Parson, professor of anatomy at the University of Aberdeen in the UK.

"All the current therapies say, 'We know you need SMN, we don't really know why, so let's just put it back,'" he said.

Researchers are interested in ways in which "downstream" stages of the complex biochemical pathway that result in damage to motor neurons could be changed to reduce symptoms.

Another approach is to look at ways to protect motor neurons, or to improve the integrity of connections between them and skeletal muscle.

Prof Parson is particularly interested in pathologies associated with the disease that do not involve the motor neurons.

These may affect the heart or the blood supply to the spinal chord.

"I don't think any of these things cause classical SMA, but they might make it worse," he said.

"They might make it progress more rapidly and they might lead to further pathologies in the future."

He said it was not clear whether the therapies being used to treat the condition at the moment will, as well as targeting the loss of SMN in motor neurons, also target non-neuronal pathologies.

Children on the current therapies may, as they become adults, develop problems with other organs, such as the kidneys, if the gene-based treatments do not alleviate these other abnormalities.

However, there is hope for further improvement in treatment despite the scientific uncertainty surrounding SMA.

"Parents' and patients' expectations have changed because they don't just want to survive," Prof Parson said.

"They want to do better and they want to be normal. Once you start improving, not surprisingly, everybody wants more."