ATMP Use Case - Spinal Muscular Atrophy (SMA)
Spinal Muscular Atrophy (SMA) is a severe and life-limiting neurodegenerative disease that leads to muscle weakness and atrophy, along with a loss of muscle reflexes. In the absence of treatment, SMA can result in premature death, depending on the disease severity. The disease’s main symptoms include progressive muscle weakness, respiratory insufficiency, and various complications such as scoliosis, contractures, nutritional issues, and the need for artificial nutrition and ventilation. Respiratory failure, requiring non-invasive ventilation, is often the life-limiting factor. However, cognitive and speech development remains fully intact.
SMA is classified into three main types based on the severity and age of onset:
1. SMA Type I (Werdnig-Hoffmann Disease): SMA Type I is the most severe form, accounting for approximately 60% of cases. Symptoms appear in infancy, typically within the first 6 months of life. These infants will not be able to sit up independently. Without treatment, 50% of patients die within the first 12 months, and 90% die within the first 2 years.
2. SMA Type II (Intermediate Form): In patients affected with SMA Type II symptoms develop between 7 and 18 months. Children with this form can sit independently but cannot walk. Life expectancy has improved significantly with non-invasive ventilation, extending into adulthood.
3. SMA Type III (Kugelberg-Welander Disease): SMA Type III is the mildest form. Motor milestones such as walking are initially achieved by affected patients. However, some patients may become wheelchair-bound in later childhood, while others lead a relatively normal life into adulthood.
When the disease manifests in the second to third decade of life, it is often referred to as Type IV. Life expectancy is only slightly reduced in these cases.
With recent advances in genetic research and the introduction of new treatments, a more refined approach of treatment has become available. Particularly important are findings related to the SMN2 gene, which acts as a disease modifier. A higher number of SMN2 gene copies (usually 2 copies) mediates a milder disease course.
Due to these genetic insights, the SMA classification has become more detailed, considering factors such as:
1. SMN2 Copy Number: A higher number of SMN2 copies is associated with a milder form of the disease.
2. Early Diagnosis and Treatment: New classifications increasingly distinguish between presymptomatic and symptomatic patients, as this significantly impacts the disease progression.
3. Subtypes Based on Genetic Mutations: Some subtypes of SMA are now more specifically termed, such as SMA Type 0, which is described as a particularly severe and early-onset form.
In Germany, approximately 1 in 6,000-10,000 newborns is diagnosed with SMA, and approximately one in 45 people is a carrier for the condition. It is estimated that there are about 1,000 to 1,500 individuals living with the disease in Germany.
Treatment Advances in SMA
Until 2016, no effective treatment for SMA was available, making it the leading genetic cause of death in infants and young children. However, in recent years significant advances have been made, particularly with disease-modifying therapies:
• Nusinersen (Spinraza®): Approved in Europe in May 2017, this drug helps improve motor function when administered early in the disease course. It can significantly improve survival and motor abilities when treatment begins before symptom onset, offering a near-normal motor development in infants who are treated immediately after birth. It is administered intrathecally (into the spinal fluid) through a lumbar puncture. Nursinersen is an antisense oligonucleotide inhibitor that targets the SMN2 gene that mediates the production of a functional SMN protein, it is not an ATMP.
• Risdiplam (Evrysdi®): In March 2021, this was the first oral treatment approved for SMA. This medication is taken daily at home and does not require hospitalization, offering a convenient treatment option. Risdiplam is a small molecule that modifies the splicing of SMN2 mRNA, increasing the production of functional survival motor neuron (SMN) protein, it is not an ATMP.
• Gene Therapy (Onasemnogene Abeparvovec – Zolgensma®): In May 2020, Europe approved the first gene therapy for SMA. This one-time administered ATMP offers the potential for cure. However, the timing of administration plays a critical role in the treatment’s success, and it is most effective when given before significant disease progression. It uses an adeno-associated virus vector (AAV9) to deliver a functional SMN1 gene directly to motor neurons, addressing the underlying cause of SMA.
These advances in ATMPs offer a new hope for individuals affected by SMA, significantly altering the course of the disease and providing a chance for a better quality of life.