Spinal Muscular Atrophy (SMA) describes a group of diseases where motor neurons of the spinal cord and brain stem, which are critical for stimulation of muscle cells, degenerate and die. Lacking the appropriate input, the muscle cells become much smaller (atrophy) and patients display symptoms of muscle weakness. Affected muscles are those involved in voluntary movement and patients may have difficulty swallowing, breathing, crawling, walking and with head/neck movement. SMA is an autosomal recessive genetic disease and for a child to be affected both parents must be carriers of the abnormal gene and both must pass this gene on to their child. The incidence of SMA is estimated at 1 in 6000 births and this condition is responsible for the death of more infants than any other genetic disease.
SMA results when the SMN1 (survival of motor neuron 1) gene, which encodes survival of motor neuron (SMN) protein, is missing or mutated. SMN is critical to the survival and health of motor neurons. The closely related survival of motor neuron SMN2 gene is retained in all SMA patients but does not produce sufficient SMN protein to prevent the development of clinical symptoms. Although SMN2 differs from SMN1 by only a single nucleotide, the change affects the efficiency with which exon 7 is incorporated into the mRNA transcript. As a result, SMN2 produces less full-length mRNA and protein than SMN1.
In 2001, researchers at Ohio State University showed that aclarubicin was able to restore levels of SMN in a mouse model by altering the incorporation of exon 7 into SMN2 transcripts. Although aclarubicin is too toxic to consider for development, the work prompted scientists at Paratek Pharmaceuticals to screen related tetracycline analogues. This has now resulted in the identification of PTK-SMA1, a synthetic tetracycline-like compound, as a lead candidate. PTK-SMA1, like aclarubicin, increases levels of SMN by correcting SMN2 splicing. The study, conducted in collaboration with scientists at Cold Spring Harbor and Rosalind Franklin Univeristy, is published in Science Translational Medicine.
Further collaborative research to progress the program to IND filing is being supported by a five-year, multi-million dollar cooperative agreement from the National Institute of Neurological Disorders and Stroke (NINDS) and by the Families of SMA funding program.