Researchers have identified a compound that helps cells produce more full-length SMN protein from the backup SMN2 gene.
Scientists have identified a chemical cousin of the commonly used antibiotic tetracycline that has the potential to be refined and modified into a therapy for spinal muscular atrophy (SMA).
PTK-SMA1 works by correcting an error in a cellular process called RNA splicing, and leads to increased production of a critical protein that is deficient in this disease.
The compound was uncovered by scientists at Rosalind Franklin University of Medicine and Science in North Chicago, Ill., Paratek Pharmaceuticals, Inc., in Boston, and Cold Spring Harbor Laboratory, in Cold Spring Harbor, N.Y. The team published its results online Nov. 4, 2009, in Science Translational Medicine.
Adrian Krainer at Cold Spring Harbor has MDA support for SMA research but did not receive MDA funding specifically for this project.
SMA causes a loss of muscle-controlling nerve cells (motor neurons) in the spinal cord and results in profound weakness or paralysis of voluntary muscles.
The molecular cause of the disease is insufficient amounts of a protein called SMN, which stands for "survival of motor neurons." The gene from which this protein is made is located on chromosome 5 and is known as SMN1.
The SMN1 gene is missing or flawed in people with SMA. However, one or more copies of a second "backup" gene, called SMN2, are also located on chromosome 5.
Normally, SMN2 genes contain a code that allows cells to omit a section known as "exon 7" during a process called RNA splicing. Exon 7 is "spliced out" before a final RNA is constructed as the genetic recipe the cell follows to make SMN protein molecules.
With exon 7 spliced out, the resulting SMN proteins are shorter than normal and highly unstable. But in a small proportion of the RNA molecules, exon 7 is correctly included in the final product, and a small amount of functional SMN protein is made from these instructions.
SMN2 cannot fully compensate for the loss of SMN1, because the amount of full-length protein generated from SMN2 is substantially lower than what would be generated from a functioning SMN1.
Increased functional SMN protein production from SMN2 is expected to have therapeutic value for SMA.
About the new findings
Scientists screened a number of tetracycline-like compounds and identified PTK-SMA1 as one that specifically stimulates the inclusion of exon 7 in the final RNA recipe.
The altered splicing led to an increase in the number of full-length SMN2 recipes, and in turn more full-length and functional SMN protein in cultured skin cells from people with SMA and in mice with an SMA-like disease. The effect was "dose-dependent," meaning the higher the dose, the greater the resulting SMN production.
Krainer, who is pursuing several lines of therapeutic development to increase SMN levels, said, "This represents the initial development of a potential drug with an apparently unique mechanism of action. It is one of several approaches being pursued in parallel to correct SMN2 gene expression. The more such drug leads that are pursued, the more likely that one or more will lead to a useful drug."
Meaning for patients
This work, Krainer said, "is a parallel approach" to other work being done, such as with gene therapy, stem cells, other classes of small molecules, or compounds called "antisense oligonucleotides." Antisense oligonucleotides stick to RNA and block genetic information, and Krainer has MDA support to develop them to change SMN2 RNA splicing.
Work on PTK-SMA1 is not as "advanced" yet as some of the other approaches, Krainer said, because the proof of principle for PTK-SMA1 has only been done in the mouse liver so far, and not yet in the central nervous system (brain and spinal cord). "Still," he said, "the novelty is that it involves targeting the splicing process with a small molecule, which in the long run could prove to be a more practical drug than an oligonucleotide."
Because PTK-SMA1 does not penetrate the barrier between the bloodstream and the central nervous system (the "blood-brain" barrier), it will need to be modified before it can be of use in SMA.
"The follow-up of this work is extensive medicinal chemistry to develop derivatives that penetrate the blood-brain barrier, and perhaps are more potent as well," Krainer said. "The more such drug leads are pursued, the more likely that one or more will lead to a useful drug."
Krainer noted that PTK-SMA1's chemical resemblance to tetracycline means that the compound already has "drug-like" properties. He cautioned, however that "unlike PTK-SMA1, tetracycline does not correct SMN2 gene expression."