Table of Contents
SMA is generally divided into sub-categories termed SMA Type 1, 2, 3 and 4. SMA, and the SMA sub-types, are diagnosed first by identifying the existence of a genetic defect in the
SMN1 gene and then determining the number of copies of the SMN2 backup gene, which correlates with
disease onset and severity. If insufficient protein is expressed, muscles do not develop properly. Approximately 60% of SMA patients have Type 1, the most severe type of SMA, with an onset
within six months of birth. Patients with SMA Type 1 have difficulty breathing and swallowing and will never develop the strength or muscle control to sit up independently or the ability to
crawl or walk. SMA Type 1 patients frequently die in early childhood due to complications related to respiratory failure resulting from motor neuron degeneration. Although SMA Types 2, 3
and 4 are generally less severe than SMA Type 1, they still present patients with significant medical challenges. We believe there is a significant unmet medical need, as there are currently no
treatments approved by the FDA for SMA. The current standard of care for patients with SMA Type 1 is limited to palliative therapies, including life-long respiratory care, ventilator support,
nutritional care, orthopedic care and physical therapy.
is caused by a genetic defect in the SMN1 gene that codes SMN, a protein necessary for survival of motor neurons. Although individuals typically receive one copy of the SMN1 gene
from each parent, only one properly functioning SMN1 gene is required to generate adequate levels of full-length SMN protein. SMA results from the patient's lack of a properly functioning SMN1 gene,
either due to mutation or loss of the gene. SMA is a recessive trait, meaning that while both parents of an SMA patient may be healthy, they each carry and pass along to their child DNA that contains
either a mutated or missing SMN1 gene which results in the disease manifesting itself in the child.
DNA contains a backup to the SMN1 gene, the SMN2 gene. Individuals may carry multiple copies of the SMN2 backup gene within their DNA. However, approximately 90% of SMN protein
produced by the SMN2 backup gene are non-functional, truncated SMN protein missing a polypeptide segment (coded for by exon 7) that is essential to form a functional SMN molecule. The
level of functional full-length SMN protein produced by an SMA patient's SMN2 genes is generally insufficient to prevent loss of proper motor neuron function. As the SMN2 genes are capable of
producing minimal levels of full-length SMN protein, the number of copies of the SMN2 backup gene serves as a disease modifier, such that the more copies of the SMN2 backup gene there are, the less
severe the disease. The following diagram presents the difference between a healthy person and someone afflicted by SMA.
is typically diagnosed based on the onset of clinical symptoms along with a genetic assessment of the absence of SMN1 and the number of copies of SMN2. However, a genetic diagnosis
can also be made prenatally either through amniocentesis or chorionic villus sampling.