Spinal muscular atrophy

What is SMA?

SMA is a genetic disorder characterized by weakness and wasting (atrophy) in muscles used for movement (skeletal muscles). It is caused by a loss of specialized nerve cells, called motor neurons, in the spinal cord and the part of the brain that is connected to the spinal cord (brainstem). The severity of symptoms and the age at which they appear vary significantly among individuals with SMA.
There are several types of SMA, classified based on the age of onset and the highest physical milestones achieved. The most common form, SMA type I, also known as Werdnig-Hoffmann disease, manifests in infants. Symptoms may be present at birth or surface within the first few months of life. These include hypotonia (poor muscle tone), weakness in the arms and legs, which is more pronounced in the legs, difficulty with movements such as sitting, crawling, and walking, and problems with swallowing and breathing.
SMA type II symptoms appear later in infancy, and children may be able to sit but not walk unaided, while SMA type III (Kugelberg-Welander disease) presents in childhood or adolescence, allowing for more mobility but still resulting in progressive muscle weakness. SMA type IV is even milder and doesn't manifest until adulthood, often allowing for a full life span.
The muscle weakness in SMA may lead to complications such as difficulty swallowing, which can cause nutritional deficiencies and aspiration (inhaling food or drink into the lungs). Respiratory muscles may also be affected, leading to an increased risk of pneumonia and other pulmonary issues. In severe cases, the muscles necessary for breathing become so weakened that ventilatory assistance is needed.

What are molecular causes of SMA?

Spinal Muscular Atrophy (SMA) is primarily caused by genetic mutations in the Survival Motor Neuron 1 (SMN1) gene, crucial for the production of the survival motor neuron (SMN) protein. The SMN protein plays an essential role in the maintenance and function of motor neurons, the nerve cells responsible for controlling voluntary muscle movement. Deficiencies in SMN protein lead to the degeneration and death of these motor neurons, resulting in the progressive muscle weakness and atrophy observed in SMA.
The SMN1 gene mutation leads to a drastic reduction in the amount of functional SMN protein. Humans have a second gene, SMN2, which also produces SMN protein but in much smaller amounts due to a single nucleotide difference that affects RNA splicing. The severity of SMA is inversely related to the number of SMN2 copies: more copies can partially compensate for the loss of SMN1 function, leading to milder forms of the disease.
Molecular mechanisms involved in SMA pathology include defects in the assembly of snRNPs (small nuclear ribonucleoproteins), which are critical for pre-mRNA splicing, and disruptions in various cellular processes, including mRNA trafficking, axonal transport, and regulation of apoptosis. The lack of SMN protein affects the overall health of motor neurons, leading to their degeneration and the subsequent muscular atrophy characteristic of SMA.

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Gene therapy solutions for SMA treatment and management

SMA is a unique example of severe genetic disorder, that have received efficient curing solution. Zolgensma (onasemnogene abeparvovec) is a groundbreaking gene therapy approved for the treatment of SMA. Zolgensma's mode of action involves delivering a functional copy of the SMN1 gene directly into a patient's cells to restore normal SMN protein levels. It uses an adeno-associated virus (AAV9) as a vector. The AAV9 vector is engineered to carry a functional copy of the SMN1 gene but is replication-deficient to ensure safety. Once administered, the vector enters the cells, and the SMN1 gene is expressed, producing the SMN protein and halting the progression of the disease.
Structurally, Zolgensma is a viral vector-based gene therapy. The AAV9 capsid envelops the recombinant DNA that encodes the human SMN protein. This design allows it to cross the blood-brain barrier, reaching motor neurons and other cells in the central nervous system, which is critical for its effectiveness in treating SMA. Zolgensma was approved by the FDA in May 2019.16:12.
Due to the immense price of such treatment, acute need for alternative gene therapeutic solutions exist. This could be achieved by AAV pseudotyping in order to create unprecedented variants of AAV-like particles.