Introduction to treatments
Spinal Muscular Atrophy (SMA) is a rare, genetic neuromuscular condition causing progressive muscle wasting (atrophy) and weakness leading to loss of movement. This may affect walking and upper body movement, breathing and swallowing. Importantly, SMA does not affect a person’s ability to think, learn or build loving relationships with others.
Does my child have SMA?
Early diagnosis means early intervention. Learn more about the symptoms of SMA here: www.signsofsma.com
Should you have any concerns, contact your child's healthcare provider without delay. Email firstname.lastname@example.org for support and more information.
What causes SMA?
Patients with the disease lack a protein called 'survival motor neuron' (SMN), which is essential for the normal functioning and survival of motor neurons. Without this protein, the motor neurons deteriorate and eventually die. This causes the muscles to fall into disuse, leading to muscle wasting (atrophy) and weakness.
The SMN protein is made by two genes, the SMN1 and SMN2 genes. Most patients with spinal muscular atrophy lack the SMN1 gene but have the SMN2 gene, which mostly produces a 'short' SMN protein which cannot work properly on its own.
There are different forms of SMA and a wide spectrum of how severely children and adults are affected. The most common form is known as ‘5q SMA’; referring to the chromosome containing the genetic cause.
When a child or adult is first diagnosed, the doctor gives a clinical classification - SMA Type I, II, III or IV - which reflects the age of onset of symptoms and the motor milestones that someone would be expected to achieve. The severity of the condition varies from person to person, both within and between ‘Types’ - each is affected differently.
Spinraza was developed by Biogen and was approved in Ireland for treating patients with SMA Types I, II or III in June 2019.
For the lower motor neurons to function and remain healthy, the cells need to produce the survival motor neuron (SMN) protein. The ability to do this is mainly controlled by the survival motor neuron 1 (SMN1) gene. The survival motor neuron 2 (SMN2) gene also contributes to the production of SMN protein, though it only makes approximately 10% of that produced by SMN1. This is also why SMN2 is often called the SMN ‘back-up’ gene.
Individuals can have multiple copies of SMN2 and, in general, it seems that those with more copies have a less severe form of SMA. Most of the SMN protein made by SMN2 is missing an important piece called exon 7. The remaining protein produced by SMN2 includes exon 7 and is the same as that made by SMN1.
Antisense oligonucleotide drugs (ASOs) are small snippets of synthetic genetic material that bind to ribonucleic acid (RNA). They are often described as molecular patches because they can be specifically designed to target and affect how a particular gene is read. ASOs have great potential for SMA, because they can accurately target the SMN2 gene to essentially convert it into the SMN1 gene, i.e. they are small molecules “patching-up” SMN2 to act more like SMN1. So they can be used to fix splicing errors in genes such as SMN2. They do this by binding to the RNA template made by SMN2 and enhancing the inclusion of exon 7 into the SMN protein.
Spinraza is an antisense oligonucleotide that targets SMN2, causing it to make more complete SMN protein.
Treatment involves a loading dose of four 12 mg injections into the spinal canal on days 0, 14, 28 and 63. This is followed by a maintenance dose of one injection every four months thereafter.
Treatment in Ireland is currently restricted to patients under 18 years old, however in November 2020 Biogen submitted an application to the NCPE (National Centre for Pharmacoeconomics) to reimburse the treatment of adults. This was an important development as adults in Ireland with SMA currently have no access to treatment. The outcome of this application process is not expected before 2023.
The gene therapy Zolgensma (onasemnogene abeparvovec) received approval for reimbursement in Ireland by the HSE in November 2021.
Patients with spinal muscular atrophy have a defect in a gene known as SMN1, which the body needs to make a protein essential for the normal functioning of nerves that control muscle movements. The active substance in Zolgensma contains a functional copy of this gene. When injected, it passes into the nerves from where it provides the correct gene to make enough of the protein and thereby restore nerve function.
Zolgensma was developed by Avexis, a pharmaceutical company now owned by Novartis Gene Therapies. The drug received EMA approval in May 2020 and is administered via a single intravenous injection. There are strict criteria as to the patients that qualify for Zolgensma, including:
- SMA type I, or presymptomatic patients with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene
- Less than 24 months old
- Weight restrictions may also apply
Similar to Spinraza, Evrysdi (Risdiplam) is an 'anti-sense oligonucleotide' medicine. It modulates how effectively the survival motor neuron 2 (SMN2) gene is used to make SMN protein. Signals (called messenger RNAs) are generated from SMN2, and the drug selectively interacts with these, resulting in more SMN protein being made by cells throughout body.
Evrysdi is administered orally, and can be taken at home. It has been trialled on a wide cohort of SMA patients, including adults into their 60s, exhibiting significant efficacy.
The European Medicines Agency approved Evrysdi in August 2021 and the treatment is currently undergoing a Health Technical Assessment in Ireland. The outcome of this process is expected in 2023.