Researchers identify drug candidates for the treatment of spinal muscular atrophy

A chemical cousin of the common antibiotic tetracycline May in the treatment of spinal muscular atrophy (SMA), a disease currently incurable, the genetic cause of main causes of death among infants is useful. This is the result of a research collaboration with Adrian Krainer, Ph.D., of Cold Spring Harbor Laboratory (CSHL) and Paratek Pharmaceuticals Scientific, and Rosalind Franklin University of Medicine and Science. SMA is caused by mutations in a gene called survival motor neuron 1 (SMN1), decreased the amount of SMN protein in motor neurons of the spinal cord - muscle cells that control activity. Degenerate Without this protein, these neurons, and infants born with the mutation and gradually lose the ability to move, swallow, breathe, and. There are no approved treatments for the treatment of SMA, which affects about 1 baby in 6000 in the United States was born.

The new molecule, promotes the levels of SMN protein in cells that fixing a bug in a mechanism of cell transformation, such as RNA splicing. In a study published in the journal "Science" Translational Medicine November 4, reported the researchers, this update, both in mouse models of SMA, as well as in cells isolated from SMA patients.

Unlike previously identified molecules that stimulate the production of SMN, tetracycline-like compound has a unique therapeutic candidate is a small molecule that specifically altered splicing of spliced directly to the reaction.

Further collaborative research will focus on the clinical development of existing drugs, and is backed by a five-year, multimillion dollar agreement of cooperation of the National Institute of Neurological Disorders and Stroke (NINDS) and by families of SMA-support program.

Splicing correction

The drug candidates target the splicing of SMN2 gene, which is essentially a backup copy of the SMN1 gene is mutated in the repair SMA patients. SMN2 not compensate for the loss of SMN1, but because it is too little functional proteins produced. Most of the protein that is produced, it lacks one important piece, without which the protein is quickly degraded.

The removal of this part of the SMN protein is due to a flaw in how the cell processes the splicing machinery of RNA copied from DNA gene, SMN2. During splicing, a complex of patterns from the RNA of certain enzymes necessary pieces called introns. Typically, the remaining exons are called necessary parts back together, together, and the edited RNA molecule is then converted into a functional protein.

In the case of the SMN2 gene, however, jumping mechanism of splicing of exon. Thus Krainer and his team have sought ways to change, splice, so that missing piece to the 7th exon is located in the latest copy of RNA.

The researchers focused on finding a class of molecules, chemical variants of tetracycline, because this class of chemicals known as RNA on the bar and change are splicing, and is less toxic than others to do the same thing.

In tests of an experimental system that the effect of molecules exclusively on splicing, the researchers examined a series of tetracycline derivatives of the chemical Paratek said. The screen shows that the PTK-Sma1 molecule is very effective for a change in splicing, such that exon 7 is included in the quoted price.

PTK-Sma1 therapy

Researchers have confirmed that the effect of PTK on Sma1-splicing exon inclusion and, ultimately, a higher level of full length and functional SMN protein. The combination of increased levels of proteins in cells of SMA patients isolated and grown in lab dishes. Scientists have also demonstrated their ability to work from in vivo injection into mice with a human SMN2 gene. The mice showed more than 5-fold increase levels of human SMN protein in the week of treatment.

"PTK-Sma1 is the only small molecule known to affect specific splicing directly and exclusively to promote the splicing reaction, Krainer said. Other molecules based on splicing and other cellular processes and thus diluting their power, and possibly the risk of side effects. PTK-Sma1 has the advantage that a derivative of tetracycline, which are not toxic and safety demonstrated in humans.

The team is on the promising with so many candidates for the therapeutic treatment of SMA and plans next to focus on two main questions are: how to find exactly PTK Sma1 redirects splicing and a means to cross the blood-brain barrier and disrupted in affected neurons in the spinal cord.