The advent of gene therapy to treat spinal muscular atrophy is a major milestone with the potential to revolutionise treatment for some rare neurological conditions.
By Eric Martin
The first few weeks of a child’s life are expected to be full of wonder and joy as the family bonds with their newest member, yet, for some parents, the growing realisation that something is not right with their child is the start of a profoundly different journey.
Spinal muscular atrophy (SMA), as the name suggests, is a condition which impacts the development, function, and degeneration of spinal motor neurons. Although it can present in adults, SMA is the most common genetic cause of death in children under the age of two in Australia.
Dr Maina Kava, a paediatric neurologist, clinical lead for neuromuscular program at Perth Children’s Hospital and the state clinical lead for mitochondrial research at the Australian Genomics Health Alliance, has been working with children affected by SMA, which has brought newfound hope to the WA families coming to terms with the diagnosis.
“At PCH, we have an excellent set-up and an extensive service that provides a multidisciplinary team approach for children affected by any neuromuscular disorder,” she said.
“The landscape of SMA is rapidly changing, with opportunities for ground-breaking treatments evolving rapidly.”
Dr Kava trained at leading institutions around the world, including India, Australia, and Canada, where she completed her neuromuscular and neuro-metabolic research before returning to Princess Margaret Hospital, making the transition with the rest of the team to PCH in June 2018.
“For me it has been a steep learning curve, seeing my first patient with SMA, extremely floppy and weak, back home in India during my paediatric rotation as an intern, but with no available treatment at that time,” she said.
New hope
“Now, years down the track, with every new patient with SMA I see, I can say something more positive, that there is hope for a potential cure, which is so much more favourable than even just five years ago when there were only the basic comfort measures, along with supportive care and a referral to palliative care.”
People with spinal muscular atrophy have insufficient levels of the survival motor neuron protein essential for the existence and functioning of motor neurons. This protein is encoded by two genes, SMN1 and SMN2, and in children with SMA, the first gene is missing.
With only the SMN2 gene present, children with SMA produce a truncated form of the protein, and having fewer copies of the SMN2 gene is associated with earlier onset of disease and more severe symptoms.
“SMA is a remarkably interesting genetic condition, where all children with the disease do not have the same phenotype,”
Dr Kava said.
About half of patients who present are babies with type 1 disease, and by the time a child presents with symptoms, they have already lost 90% of their neurons.
“This means there are significant differences in the way they present. Some children could have completely normal motor functions, and they may not start exhibiting symptoms until late adulthood, or they may be children who are born with a significant neuro-motor deficit and are not able to move their muscles.
“These children require ventilation or respiratory support to help them with their breathing as soon as they are born and, clinically, we used to classify them as a type zero, which meant children who were presenting with symptoms right
at birth.”
SMA is classified into four types depending on the age of onset and its impact on motor function:
- Type 1 – onset 0-6 months, life expectancy is less than two years
- Type 2 – onset 6-18 months, life expectancy is 10-40 years
- Type 3 – onset after 18 months, life expectancy into adulthood
- Type 4 – onset after five years, life expectancy into adulthood.
About half of patients who present are babies with type 1 disease, and by the time a child presents with symptoms, they have already lost 90% of their neurons.
“Children with type 1 SMA can present any time between six weeks to six months. They have significant motor dysfunction, and in most cases, they are not able to sit. 80% of these children die before the age of two years,” Dr Kava said.
“Of all the types of SMA we see in our clinic, Type 2 is the most common phenotype. These children present between 6-18 months of age. They may have initially attained some milestones, such as head control, or the ability to sit upright, but they cannot stand or walk.”
“There is an increased risk of early mortality because there is a significant association with spinal deformity and weak bulbar and respiratory function, which eventually leads to death of these beautiful children.”
“Seemingly simple things like swallowing, breathing, and feeding is affected, and eventually leads to poor nutrition and associated micro-aspiration of food into the lungs, causing chemical pneumonitis and pneumonia, and all kinds of respiratory dysfunction.”
Dr Kava explained that parents are carriers, and in Australia, there is an incidence of about one in 10,000 live births.
“Usually, we expect about three to four small children with SMA each year, but it varies, as some years we have had none and some years we have had many.”
PCH started its Nusinersen drug program in November 2017 and Dr Kava and her team now have five years’ experience of treating children with the synthetic antisense oligonucleotide, otherwise known as Spinraza.
Nusinersen enables the SMN2 gene to produce a full length SMN protein and has been shown to improve motor function in several trials with participants aged from 30 days to 15 years. However, as the drug’s terminal half-life in cerebrospinal fluid is just 19-25 weeks, the 12mg dose, which is delivered by lumbar puncture, needs to be regularly re-administered.
“Nusinersen is the first treatment approved for all types of SMA and helps in the production of the survival motor neuron protein. Although it needs to be administered intrathecally, it has been proven to be safe,” Dr Kava said.
“In all the clinical trials, and from our own experience, having done more than 200 injections now – we found that children tolerate the procedure very well.”
The next breakthrough to occur, she said, was the advent of an oral medication, Risdiplam, a modifier of pre-mRNA splicing which also enables the production of full-length SMN proteins, but one which can only be used in SMA patients who have at least two copies of the SMN2 gene.
Risdiplam can cross the blood-brain barrier and is metabolised by several enzymes including cytochrome P450 (CYP) 3A4, and the dose is determined by the age and weight of the child.
However, even though Risdiplam is easier to administer than Nusinersen, the drug’s effect on pre-mRNA splicing is not confined to the gene coding for SMN, and though no causal link was shown, three infants died from respiratory complications during the FIREFISH trial.
The drug also needs to be administered every day for the rest of the patient’s life.
A year ago, the PBS listed what is currently the most expensive drug on PBS, Onasemnogene Abeparvovec, which is a SMN1 gene therapy given as an intravenous injection along with a viral vector to enable the gene to reach the spinal motor neurons.
“Genetically, it is an extraordinarily complex technique, and currently, the drug is imported from the US. Up until now we needed to send babies interstate to Sydney or Melbourne to access gene therapy, but as of August 2022, we are able to offer gene therapy at PCH.
“Thanks to the support of PCH executives, we are the third site for gene therapy in the country, and we now have a supply agreement in place with the drug company, Novartis.”
The genetically engineered version of the SMN1 gene is now on the PBS and available for children with SMA under the age of nine months, yet much like Risdiplam, the weight dependent dosage can result in complications.
“We must be mindful that gene therapy, even though it is genetically based, is still a therapy and not a cure. It helps maintain motor function, but it does not take the disease away. The child still has SMA and will continue to need physiotherapy and regular monitoring in the neuromuscular clinic.”
Changing the message
But Dr Kava stressed the importance of now having a positive message that clinicians can give along with a diagnosis.
“Until a few years ago, when we had a child with a diagnosis of SMA, we were giving them a prognosis (depending on the type of SMA they had) that often included saying things like, ‘your child is never going to walk, they are going to be in a wheelchair for the rest of their life, and that their life span will not be great’,” she said.
“These are things which are heartbreaking to share, and it is a devastating, progressive disease. But having a treatment which can just maintain the disease progress is an important thing, such as having a child who has started to walk will hopefully continue to walk once treatment is initiated.
“We want to help them to become as functional as possible because the most important thing about SMA is that these children have no intellectual problems. They are in the company of adults and therapists and their IQ is often much higher than those of other children.
“They have so many cognitive skills, but unfortunately, the muscle weakness prevents them from doing things. The children are completely aware of everything, they have normal intellectual function, and then they deteriorate right in front of your eyes.
“Just preserving what they have (in terms of movement) makes a substantial difference for them because that enables them to function to their full capacity, to be their best, and that is so satisfying for everyone involved.
“And that is why we advocate for initiating treatment early, which is what led to the newborn screening program.”
Newborn screening for SMA from dried blood spot started in January this year, and it is currently the only condition on the NBS panel which is picked up by genetic testing.
Vital role of GPs
WA is the second state to have implemented the newborn screening, and while the program has already detected SMA in two infants, Dr Kava stressed that GPs were the backbone of the medical system in Australia and had a significant role to play in the detection and management of SMA.
“Even though we have newborn screening, there are still children out in the community who may have type two, type three, or type four SMA, and these children are going to present with symptoms at some stage,” she said.
“We must also be mindful that we have children at the clinic who do not have Medicare support and are managed by their GPs, who play an important role in terms of following up the children for immediate care after starting medications and making sure the family as a unit is well looked after.”
One of the most important tools for GPs was a neuromuscular hotline.
“My aim is to have a zero-wait time for any child suspected of SMA and if a GP anywhere in WA suspects a child who has hypotonia or absent reflexes could potentially have SMA, they should ring our hotline and contact us,” Dr Kava said.
“We will help assess the child and decide the best course of action. We do involve the GPs in the management, and we endeavour to help guide and support them.”
Dr Kava said that gene therapy had revolutionised the area for many neurodegenerative conditions.
“So much is changing in neuromuscular genetics, and it is a field to watch,” she said.
“It has been such an amazing journey to be able to come from seeing a child with SMA and giving them a diagnosis for this devastating disease, to now, being able to identify this condition even before it starts presenting with symptoms and then prevent them from occurring.